Apolipoprotein A-I mimics

ABSTRACT

Provided are peptides, compositions thereof, and methods for treating or preventing dyslipidemia, a cardiovascular disease, endothelial dysfunction, a macrovascular disorder, or a microvascular disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/705,094, filed Feb. 12, 2010, which claims the benefit of priorityfrom U.S. Provisional Application Ser. Nos. 61/152,962, filed Feb. 16,2009, 61/152,966, filed Feb. 16, 2009, and 61/152,960, filed Feb. 16,2009, each of which is herein incorporated by reference in its entirety.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith areincorporated herein by reference in their entirety: A computer readableformat copy of the Sequence Listing (filename:CERE_(—)002_(—)07US_SubSeqList.txt, date recorded: Apr. 30, 2013, filesize 202 kilobytes).

FIELD OF THE INVENTION

The invention provides peptides, compositions thereof, and methods fortreating or preventing dyslipidemia, a cardiovascular disease,endothelial dysfunction, a macrovascular disorder, or a microvasculardisorder.

BACKGROUND OF THE INVENTION

Cholesterol circulating in the human body is carried by plasmalipoproteins, which are particles of complex lipid and proteincomposition that transport lipids in the blood. Two types of plasmalipoproteins that carry cholesterol are low density lipoproteins (“LDL”)and high density lipoproteins (“HDL”). LDL particles are believed to beresponsible for the delivery of cholesterol from the liver (where it issynthesized or obtained from dietary sources) to extrahepatic tissues inthe body. HDL particles, on the other hand, are believed to aid in thetransport of cholesterol from the extrahepatic tissues to the liver,where the cholesterol is catabolized and eliminated. Such transport ofcholesterol from the extrahepatic tissues to the liver is referred to as“reverse cholesterol transport.”

The reverse cholesterol transport (“RCT”) pathway has three main steps:(i) cholesterol efflux, i.e., the initial removal of cholesterol fromvarious pools of peripheral cells; (ii) cholesterol esterification bythe action of lecithin:cholesterol acyltransferase (“LCAT”), therebypreventing a re-entry of effluxed cholesterol into cells; and (iii)uptake of the cholesteryl ester by HDL and delivery of theHDL-cholesteryl ester complex to liver cells.

The RCT pathway is mediated by HDL particles. Each HDL particle has alipid component and a protein component. The lipid component of HDL canbe a phospholipid, cholesterol (or a cholesterol ester), or atriglyceride. The protein component of HDL is primarily made up ofApoA-I. ApoA-I is synthesized by the liver and small intestine aspreproapolipoprotein which is secreted as a proprotein that is rapidlycleaved to generate a mature polypeptide having 243 amino acid residues.ApoA-I is primarily made up of 6 to 8 different repeat units made up of22 amino acid residues spaced by a linker moiety which is often proline,and in some cases is a moiety made up of several residues. ApoA-I formsthree types of stable complexes with lipids: small, lipid-poor complexesreferred to as pre-β-1 HDL; flattened discoidal particles containingpolar lipids (phospholipid and cholesterol) referred to as pre-β-2 HDL;and spherical particles containing both polar and nonpolar lipids,referred to as spherical or mature HDL (HDL₃ and HDL₂).

Attempts have been made to recombinantly produce and administer ApoA-Ito patients to protect against atherosclerotic disease. However, thereare many pitfalls associated with the production and use of ApoA-I,making it less than ideal as a drug; e.g., ApoA-I is a large proteinthat is difficult and expensive to produce, and significantmanufacturing and reproducibility problems must be overcome with respectto stability during storage, delivery of an active product and half-lifein vivo.

In view of these drawbacks, attempts have been made to produce peptidesthat can mimic the activity of ApoA-I in vivo. There is a need in theart for the development of additional peptides that can mimic theactivity of ApoA-I in vivo, which are simple and cost-effective toproduce.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides 22- to 29-residue peptideshaving the following Formula IR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is an achiral, D-, or L-basic amino acid residue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 15- to 22-residue peptideshaving the following Formula IIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—Y²R²,  FormulaIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is an achiral, D-, or L-basic amino acid residue;

X² is Leu or D-Leu;

X³ is an achiral, D-, or L-basic amino acid residue;

X⁴ is Gln, Asn, D-Gln, or D-Asn;

X⁵ is Leu, D-Leu, or an achiral, D-, or L-basic amino acid amino acidresidue;

X⁶ is Leu, Trp, Phe, D-Leu, D-Trp, or D-Phe;

X⁷ is an achiral, D-, or L-acidic amino acid residue;

X⁸ is Asn, D-Asn, or an achiral, D-, or L-acidic amino acid residue;

X⁹ is Leu, Trp, D-Leu, or D-Trp;

X¹⁰ is Leu, Trp, D-Leu, or D-Trp;

X¹¹ is an achiral, D-, or L-acidic amino acid residue;

X¹² is an achiral, D-, or L-basic amino acid residue;

X¹³ is Leu, Phe, D-Leu, or D-Phe;

X¹⁴ is Leu, Phe, D-Leu, or D-Phe;

X¹⁵ is an achiral, D-, or L-acidic amino acid residue;

X¹⁶ is Leu or D-Leu;

X¹⁷ is an achiral, D-, or L-aliphatic amino acid residue;

X¹⁸ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 4 residues;

Y² is absent;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to three of residues X¹ to X¹⁷ are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 22- to 29-residue peptideshaving the following Formula IIIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIIIor a pharmaceutically acceptable salt thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is Leu or D-Leu;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is an achiral, D-, or L-basic amino acid residue;

X⁶ is Gln, Asn, D-Gln, or D-Asn;

X⁷ is Leu or D-Leu;

X⁸ is Ala or D-Ala;

X⁹ is Asp or D-Asp;

X¹⁰ is Leu, Phe, Gly, D-Leu, or D-Phe;

X¹¹ is Gly, Leu, or D-Leu;

X¹² is Arg or D-Arg;

X¹³ is an achiral, D-, or L-acidic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu or D-Leu;

X¹⁶ is Gln or D-Gln;

X¹⁷ is Glu, Leu, D-Glu, or D-Leu;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is an achiral, D-, or L-aliphatic amino acid residue; X²⁰ is Glu orD-Glu;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue;

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is a D-amino acid residue, except thatone or more of each chiral terminal amino acid residue and each chiralamino acid residue immediately adjacent thereto is an L-amino acidresidue.

A peptide of Formula I, II, or III, or a pharmaceutically acceptablesalt thereof (an “ApoA-I Mimic”) is useful for treating or preventingdyslipidemia, a cardiovascular disease, endothelial dysfunction, amacrovascular disorder, or a microvascular disorder (each being a“Condition”).

In another embodiment, the invention provides compositions comprising aneffective amount of an ApoA-1 Mimic and a pharmaceutically acceptablecarrier or vehicle.

In another embodiment, the invention provides methods for treating orpreventing a Condition, comprising administering an effective amount ofan ApoA-I Mimic to a mammal in need thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is a Schiffer-Edmundson helical wheel diagram of an idealizedamphipathic α-helix in which open circles represent hydrophilic aminoacid residues and shaded circles represent hydrophobic amino acidresidues.

FIG. 1B is a helical net diagram of the idealized amphipathic helix ofFIG. 1A.

FIG. 1C is a helical cylinder diagram of the idealized amphipathic helixof FIG. 1A.

FIG. 2 is a Schiffer-Edmundson helical wheel diagram of Segrest'sconsensus 22-mer peptide (SEQ ID NO. 1)

FIG. 3A illustrates a tertiary-order branched network of the ApoA-IMimics.

FIG. 3B illustrates a quaternary-order branched network of the ApoA-IMimics.

FIG. 3C illustrates a mixed-order branched network of the ApoA-I Mimics.

FIG. 3D illustrates exemplary “Lys-tree” branched networks of the ApoA-IMimics.

FIG. 4A is a cartoon depicting the various aggregation states andpeptide-lipid complexes that can be obtained with the ApoA-I Mimics ofthe invention. Left: Multimerization process of the peptides resultingfrom the interaction of several peptide helices and leading to theformation of oligomers in conditions of defined peptide concentration,pH and ionic strength. Center: The interaction of the ApoA-I Mimics (inany of these states of aggregation) with lipidic entities (such as smallunilamellar vesicles (“SUVs”)) leads to lipid reorganization. Right: Bychanging the lipid:peptide molar ratio, different types of peptide-lipidcomplexes can be obtained, from lipid-peptide comicelles at lowlipid-peptide ratios, to discoidal particles and finally to largemultilamellar complexes at increasingly higher lipid:peptide ratios.

FIG. 4B illustrates the generally-accepted model for discoidal ApoA-IMimic-lipid complexes formed in a defined range of lipid:ApoA-I Mimicratios. Each ApoA-I Mimic surrounding the disc edge is in close contactwith its two nearest neighbors.

FIG. 5 is a representative gel permeation chromatogram for a Peptide 16(SEQ ID NO: 16)/lipid complex (the lipids being sphingomyelin, DPPC, andDPPG).

FIG. 6 is a plot of baseline increase in HDL fraction of totalcholsterol following administration of a Peptide 16 (SEQ ID NO:16)/lipid complex (the lipids being sphingomyelin, DPPC, and DPPG, andthe components being present in a weight ratio of Peptide 16 (SEQ ID NO:16):sphingomyelin:DPPC:DPPG of 1:1.35:1.35:0.30) to rabbits.

FIG. 7 is a plot of increase in HDL fraction of free cholsterolfollowing administration of a Peptide 16 (SEQ ID NO: 16)/lipid complex(the lipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)to rabbits.

FIG. 8 is a gel permeation chromatography elution profile at baseline(dark line) and 20 min after administration of 2.5 mg/kg of a Peptide 16(SEQ ID NO: 16)/lipid complex (the lipids being sphingomyelin, DPPC, andDPPG in a weight ratio of 1:1.2125:1.2125:0.075, and the peptide:lipidweight ratio being 1:2.5) to rabbits.

FIG. 9 is a plot of increase in plasma phospholipid following infusionof a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma phospholipidlevels were measured. Baseline values (ranging from 0.96 to 1.18 g/L forthe four groups) were subtracted to determine the increase in plasmaphospholipid levels. There were 3 animals per group. By 30-34 hours postdose the values had returned to a value at or below baseline.

FIG. 10A is a plot of increase in plasma total cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma totalcholesterol levels were measured. Baseline values were subtracted todetermine the increase in cholesterol levels. The baseline values rangedfrom 0.59 to 0.77 g/L. There were 3 animals per group. By 30-34 hourspost dose the values had returned to a value at or below baseline.

FIG. 10B is a plot of increase in plasma free cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma freecholesterol levels were measured. Baseline values were subtracted todetermine the increase in cholesterol levels. The baseline values rangedfrom 0.21 to 0.27 g/L. There were 3 animals per group. By 30-34 hourspost dose the values had returned to a value at or below baseline.

FIG. 10C is a plot of increase in plasma esterified cholesterolfollowing infusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma esterifiedcholesterol levels were measured. Baseline values were subtracted todetermine the increase in cholesterol levels. The baseline values rangedfrom 0.39 to 0.52 g/L. There were 3 animals per group. By 30-34 hourspost dose the values had returned to a value at or below baseline.

FIG. 11A is a plot of increase in plasma HDL total cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma HDL totalcholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline HDL total cholesterolranged from 0.33 to 0.38 g/L. There were 3 animals per group. By 30-34hours post dose the values had returned to a value at or below baseline.

FIG. 11B is a plot of increase in plasma HDL free cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma HDL freecholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline HDL free cholesterol rangedfrom 0.11 to 0.13 g/L. There were 3 animals per group. By 30-34 hourspost dose the values had returned to a value at or below baseline.

FIG. 11C is a plot of increase in plasma LDL total cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma LDL totalcholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline LDL total cholesterolranged from 0.17 to 0.33 g/L. There were 3 animals per group. By 30-34hours post dose the values had returned to a value at or below baseline.

FIG. 11D is a plot of increase in plasma LDL free cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma LDL freecholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline LDL free cholesterol rangedfrom 0.06 to 0.11 g/L. There were 3 animals per group. By 30-34 hourspost dose the values had returned to a value at or below baseline.

FIG. 11E is a plot of increase in plasma VLDL total cholesterolfollowing infusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma VLDL totalcholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline VLDL total cholesterolranged from 0.04 to 0.11 g/L. There were 3 animals per group. By 30-34hours post dose the values had returned to a value at or below baseline.

FIG. 11F is a plot of increase in plasma VLDL free cholesterol followinginfusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma VLDL freecholesterol was measured. Baseline values were subtracted to determinethe increase in cholesterol levels. Baseline VLDL free cholesterolranged from 0.02 to 0.04 g/L. There were 3 animals per group. By 30-34hours post dose the values had returned to a value at or below baseline.

FIG. 12 is a plot of the increase in plasma triglyceride levelsfollowing infusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 10 (triangle), 20 (circle)or 30 (diamond) mg/kg. At various times post dose, plasma triglyceridelevels were measured. Baseline values (ranging from 0.40 to 0.80 g/L forthe four groups) were subtracted to determine the increase in plasmatriglyceride levels. There were 3 animals per group.

FIG. 13 is a plot of the increase in plasma HDL free cholesterol levelsfollowing infusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at doses of 0 (square), 2.5 (triangle), 5 (circle)or 10 (diamond) mg/kg. At baseline and 5, 20, 40, 60, 90 and 120 minutesafter initiating the infusion, plasma HDL free cholesterol levels weremeasured. Baseline values were subtracted to determine the increase inplasma HDL free cholesterol levels. There were 4 animals per group.

FIG. 14A is a plot of an HPLC gel permeation chromatography elutionprofile at baseline (dark line) and 20 min after infusion of 2.5 mg/kgPeptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5).Shown on the Y-axis is the absorption from the inline free cholesterolassay of the lipoprotein fractions eluting from the HPLC gel permeationchromatography. The peaks from left to right correspond to the VLDL, LDLand HDL fractions.

FIG. 14B is a plot of an HPLC gel permeation chromatography elutionprofile at baseline (dark line) and 20 min after infusion of 5.0 mg/kgPeptide 16 (SEQ ID NO: 16)/lipid complex (the lipids beingsphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5).Shown on the Y-axis is the absorption from the inline free cholesterolassay of the lipoprotein fractions eluting from the HPLC gel permeationchromatography. The peaks from left to right correspond to the VLDL, LDLand HDL fractions.

FIG. 15 is a plot of the increase in plasma HDL free cholesterol levelsfollowing infusion of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)into fasted rabbits at a dose of 20 mg/kg at a rate of 1 mL/min(triangles) or 0.2 mL/min (diamonds). At various times post dose, plasmaHDL free cholesterol levels were measured. Baseline values weresubtracted to determine the increase in plasma HDL free cholesterollevels. There were 4 animals per Peptide 16 (SEQ ID NO: 16)/lipidcomplex treatment group, while there were 2 animals per vehicletreatment group.

FIG. 16 illustrates plots of the kinetic profiles of Peptide 16 (SEQ IDNO: 16) (upper panels), free cholesterol (middle panels) andphospholipid (lower panels) in male and female rats following first doseadministration of Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipidsbeing sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)on Day 0. The decrease of Peptide 16 (SEQ ID NO: 16) and phospholipidlevels in plasma over time indicate the clearance of Peptide 16 (SEQ IDNO: 16)/lipid complex. The kinetics of free cholesterol are presented.Each data point represents the average±SD (N=3 rats/group).

FIG. 17 illustrates plots of the kinetic profiles of Peptide 16 (SEQ IDNO: 16) (upper panels), free cholesterol (middle panels) andphospholipid (lower panels) in male and female rats following multipledose administration of Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)on Day 26. These animals received Peptide 16 (SEQ ID NO: 16)/lipidcomplex every second day for 4 weeks. The decrease of Peptide 16 (SEQ IDNO: 16) and phospholipid levels in plasma over time indicate theclearance of Peptide 16 (SEQ ID NO: 16)/lipid complex. The kinetics offree cholesterol are presented. Each data point represents theaverage±SD (N=3 rats/group).

FIG. 18 illustrates plots of the kinetic profiles of Peptide 16 (SEQ IDNO: 16) (upper panels), free cholesterol (middle panels) andphospholipid (lower panels) in male and female cynomolgus monkeysfollowing first dose administration of Peptide 16 (SEQ ID NO: 16)/lipidcomplex (the lipids being sphingomyelin, DPPC, and DPPG in a weightratio of 1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being1:2.5) on Day 0. The decrease of Peptide 16 (SEQ ID NO: 16) andphospholipid levels in plasma over time indicate the clearance ofPeptide 16 (SEQ ID NO: 16)/lipid complex. The kinetics of freecholesterol are presented. Each data point represents the average±SD(N=3 monkeys/group).

FIG. 19 illustrates plots of the kinetic profiles of Peptide 16 (SEQ IDNO: 16) (upper panels), free cholesterol (middle panels) andphospholipid (lower panels) in male and female cynomolgus monkeysfollowing multiple dose administration of Peptide 16 (SEQ ID NO:16)/lipid complex (the lipids being sphingomyelin, DPPC, and DPPG in aweight ratio of 1:1.2125:1.2125:0.075, and the peptide:lipid weightratio being 1:2.5) on Day 26. These animals received Peptide 16 (SEQ IDNO: 16)/lipid complex every second day for 4 weeks. The decrease ofPeptide 16 (SEQ ID NO: 16) and phospholipid levels in plasma over timeindicate the clearance of Peptide 16 (SEQ ID NO: 16)/lipid complex. Thekinetics of free cholesterol are presented. Each data point representsthe average±SD (N=3 monkeys/group).

FIG. 20A is a plot of the % of increase from the pre-dose value ofplasma total cholesterol in C57B1/6J mice after treatment with theFormulation A, B, or C. 6 animals/per group were sequencially sampled atdifferent time points.

FIG. 20B is a plot of the increase in plasma total cholesterol inC57B1/6J mice after treatment with the Formulation A, B, or C. 6animals/per group were sequencially sampled at different time points.

FIG. 21A is a plot of the % of increase from the pre-dose value ofplasma esterified cholesterol in C57B1/6J mice after treatment with theFormulation A, B, or C. 6 animals/per group were sequencially sampled atdifferent time points.

FIG. 21B is a plot of the increase in plasma esterified cholesterol inC57B1/6J mice after treatment with the Formulation A, B, or C. 6animals/per group were sequencially sampled at different time points.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“About,” when immediately preceding a number or numeral means that thenumber or numeral ranges plus or minus 10%. For example, “about 1:1”ranges from 0.9:1 to 1.1:1.

“Alkyl,” as used herein unless otherwise defined, refers to anoptionally substituted saturated branched, straight chain or cyclichydrocarbon radical. Typical alkyl groups are (C₁-C₆) alkyl groups thatinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, and the like. Insome embodiments, the alkyl groups are (C₁-C₄) alkyl. Unless specifiedotherwise, the alkyl is unsubstituted.

“Alkenyl,” as used herein unless otherwise defined, refers to anunsaturated branched, straight chain or cyclic non-aromatic hydrocarbonradical having one or more carbon-carbon double bonds. The one or moredouble bonds can be in either the cis or trans conformation. Typicalalkenyl groups include, but are not limited to, ethenyl, propenyl,isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl andthe like. In some embodiments, the alkenyl group is (C₂-C₆) alkenyl.

“Alkynyl,” as used herein unless otherwise defined, refers to anunsaturated branched or straight chain hydrocarbon radical having atleast one carbon-carbon triple bond. Typical alkynyl groups include, butare not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl,hexynyl and the like. In some embodiments, the alkynyl group is (C₂-C₆)alkynyl.

“Aryl,” as used herein unless otherwise defined, refers to an optionallysubstituted aromatic ring system in which each atom within the ring isC, O, N, or S, thus encompassing heterocyclic aromatic rings. Typicalaryl groups include, but are not limited to benzyl, phenyl, naphthyl,anthracyl, furan, imidazole, indazole, indole, isoquinoline,isothiazole, isoxazole, pyran, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine,quinoxaline, thiazole, and thiophene. In some embodiments, the arylgroup is (C₅-C₂₆ aryl). In some embodiments, a heteroaryl group is a5-20-membered heteroaryl. In other embodiments, a heteroaryl group is5-10-membered heteroaryl. Unless specified otherwise, the aryl isunsubstituted.

“Aralkyl,” as used herein unless otherwise defined, refers to an alkylgroup substituted with an aryl group.

“Substituted Alkyl or Aryl,” as used herein unless otherwise defined,refers to an alkyl or aryl group in which one or more of its hydrogenatoms are replaced with another substituent. Typical substituentsinclude —OR^(a), —SR^(a), —NR^(a)R^(a), —NO₂, —CN, halogen, —SO₂R^(a),—C(O)R^(a), —C(O)OR^(a) and —C(O)NR^(a)R^(a), where each R^(a) isindependently hydrogen, alkyl, or aryl.

“Hydrophilic face,” as used herein unless otherwise defined, refers to aface of the helix having overall net hydrophilic character.

“Hydrophobic face,” as used herein unless otherwise defined, refers to aface of the peptide having overall net hydrophobic character.

As used herein when referring to an ApoA-I Mimic, the number of terminal—NH₂ groups is zero where R¹ is an amino protecting group and is 1 whereR¹ is H.

As used herein when referring to an ApoA-1 Mimic, the number ofterminal-COOH groups is zero where R² is a carboxyl protecting group andis 1 where R² is OH.

A “mammal,” as used herein unless otherwise defined, refers to a human,mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate,such as a monkey, chimpanzee, or baboon. In one embodiment, the mammalis a human.

An “effective amount,” when used in connection with an ApoA-I Mimic isan amount that is effective for treating or preventing a Condition.

“HDL free cholesterol,” as used herein means the amount of cholesterolhaving a free hydroxyl group (“free cholesterol”) that is containedwithin HDL particles in the serum. The HDL particles can be formed froman ApoA-I Mimic/lipid complex.

“HDL total cholesterol,” as used herein means the amount of freecholesterol plus the amount of cholesterol having a hydroxyl group thathas been esterified (“esterified cholesterol”) that is contained withinHDL particles in the serum. The HDL particles can be formed from anApoA-I Mimic/lipid complex.

“Amino acid residue,” as used herein unless otherwise defined, includesgenetically encoded amino acid residues and non-genetically encodedamino acid residues.

Abbreviations for the genetically encoded amino acid residues as usedherein are set forth in Table 1 below.

TABLE 1 Amino Acid One-Letter Abbreviation Three-Letter AbbreviationAlanine A Ala Arginine R Arg Asparagine N Asn Aspartic acid D AspCysteine C Cys Glutamine Q Gln Glutamic acid E Glu Glycine G GlyHistidine H His Isoleucine I Ile Leucine L Leu Lysine K Lys Methionine MMet Phenylalanine F Phe Proline p Pro Serine S Ser Threonine T ThrTryptophan W Trp Tyrosine Y Tyr Valine V Val

Non-genetically encoded amino acid residues include, but are not limitedto, β-alanine (β-Ala); 2,3-diaminopropionic acid (Dpr); nipecotic acid(Nip); pipecolic acid (Pip); ornithine (Orn); citrulline (Cit);t-butylalanine (t-BuA); 2-t-butylglycine (t-BuG); N-methylisoleucine(Melle); phenylglycine (PhG); cyclohexylalanine (ChA); norleucine (Nle);naphthylalanine (NaI); 4-chlorophenylalanine (Phe(4-Cl));2-fluorophenylalanine (Phe(2-F)); 3-fluorophenylalanine (Phe(3-F));4-fluorophenylalanine (Phe(4-F)); penicillamine (Pen);1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic);β-2-thienylalanine (Thi); methionine sulfoxide (MSO); homoarginine(hArg); N-acetyl lysine (AcLys); 2,4-diaminobutyric acid (Dbu);2,3-diaminobutyric acid (Dab); p-aminophenylalanine (Phe (pNH₂));N-methyl valine (MeVal); homocysteine (hCys), homophenylalanine (hPhe);homoserine (hSer); hydroxyproline (Hyp); homoproline (hPro); and thecorresponding D-enantiomer of each of the foregoing, e.g., D-Ala, D-Dpr,D-Nip, D-Orn, D-Cit, D-t-BuA, D-t-BuG, D-Melle, D-PhG, D-ChA, D-Nle,D-NaI, D-Phe(4-Cl), D-Phe(2-F), D-Phe(3-F), D-Phe(4-9, D-Pen, D-Tic,D-Thi, D-MSO, D-hArg, D-AcLys, D-Dbu, D-Dab, D-Phe(pNH₂), D-MeVal,D-hCys, D-hPhe, D-hSer, D-Hyp, and D-hPro. Other non-genetically encodedamino acid residues include 3-aminopropionic acid; 4-aminobutyric acid;isonipecotic acid (lnp); aza-pipecolic acid (azPip); aza-proline(azPro); α-aminoisobutyric acid (Aib); ε-aminohexanoic acid (Aha);δ-aminovaleric acid (Ava); N-methylglycine (MeGly).

“Chiral,” as used herein to refer to an amino acid residue, means anamino acid residue having at least one chiral center. In one embodiment,the chiral amino acid residue is an L-amino acid residue. Examples ofL-amino acid residues include, but are not limited to, Ala, Arg, Asn,Asp, Cys, Gln, Glu, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp,Tyr, Val, p-Ala, Dpr, Nip, Orn, Cit, t-BuA, t-BuG, Melle, PhG, ChA, Nle,NaI, Phe(4-Cl), Phe(2-F), Phe(3-F), Phe(4-F), Pen, Tic, Thi, MSO, hArg,AcLys, Dbu, Dab, Phe(pNH₂), MeVal, hCys, hPhe, hSer, Hyp, and hPro. Inone embodiment, the chiral amino acid residue is a D-amino acid residue.Examples of D-amino acid residues include, but are not limited to D-Ala,D-Arg, D-Asn, D-Asp, D-Cys, D-Gln, D-Glu, D-His, D-Ile, D-Leu, D-Lys,D-Met, D-Phe, D-Pro, D-Ser, D-Thr, D-Trp, D-Tyr, D-Val, D-β-Ala, D-Dpr,D-Nip, D-Pip, D-Orn, D-Cit, D-t-BuA, D-t-BuG, D-MeIle, D-PhG, D-ChA,D-Nle, D-NaI, D-Phe(4-Cl), D-Phe(2-F), D-Phe(3-F), D-Phe(4-F), D-Pen,D-Tic, D-Thi, D-MSO, D-hArg, D-AcLys, D-Dbu, D-Dab, D-Phe (pNH₂),D-MeVal, D-hCys, D-hPhe, D-hSer, D-Hyp, and D-hPro.

“Achiral,” as used herein to refer to an amino acid residue, means anamino acid residue that does not have a chiral center. Examples ofachiral amino acid residues include, but are not limited to, Gly, Inp,Aib, Aha, Ava, MeGly, azPip, and azPro.

“Aliphatic amino acid residue,” as used herein unless otherwise defined,refers to an amino acid residue having an aliphatic hydrocarbon sidechain. Aliphatic amino acid residues include, but are not limited to,Ala (A), Val (V), Leu (L), Ile (I), Pro (P), azPro, Pip, azPip, β-Ala,Aib, t-BuA, t-BuG, MeIle, ChA, Nle, MeVal, Inp, Nip, hPro, D-Ala, D-Val,D-Leu, D-Ile, D-Pro, D-β-Ala, D-t-BuA, D-t-BuG, D-Melle, D-Nle, D-MeVal,D-Nip, D-Pip, D-ChA, and D-hPro. In one embodiment, the aliphatic aminoacid residue is an L-amino acid residue. In another embodiment, thealiphatic amino acid residue is a D-amino acid residue. In anotherembodiment, the aliphatic amino acid residue is an achiral amino acidresidue.

“Hydrophilic amino acid residue,” as used herein unless otherwisedefined, refers to an amino acid residue exhibiting a hydrophobicity ofless than zero according to the normalized consensus hydrophobicityscale of Eisenberg et al., 1984, J. Mol. Biol. 179:125-142. Hydrophilicamino acid residues include, but are not limited to, Pro (P), Gly (G),Thr (T), Ser (S), His (H), Glu (E), Asn (N), Gln (O), Asp (D), Lys (K)Arg (R), Dpr, Orn, Cit, Pen, MSO, hArg, AcLys, Dbu, Dab, Phe(p-NH₂),hCys, hSer, Hyp, D-Pro, D-Thr, D-Ser, D-His, D-Glu, D-Asn, D-Gln, D-Asp,D-Lys, D-Arg, D-Dpr, D-Orn, D-Cit, D-Pen, D-MSO, D-hArg, D-AcLys, D-Dbu,D-Dab, D-Phe(p-NH₂), D-hCys, D-hSer, and D-Hyp. Other hydrophilic aminoacid residues include, but are not limited to, C₁₋₄ lateral chainanalogs having the following formulas:

wherein n is an integer from 1 to 4. In one embodiment, the hydrophilicamino acid residue is an L-amino acid residue. In another embodiment,the hydrophilic amino acid residue is a D-amino acid residue. In anotherembodiment, the hydrophilic amino acid residue is an achiral amino acidresidue. In another embodiment, the hydrophilic amino acid residue is anacidic L-amino acid residue, an acidic D-amino acid residue, or anacidic achiral amino acid residue. In another embodiment, thehydrophilic amino acid residue is a basic L-amino acid residue, a basicD-amino acid residue, or a basic achiral amino acid residue.

“Hydrophobic amino acid residue,” as used herein unless otherwisedefined, refers to an amino acid residue exhibiting a hydrophobicity ofgreater than zero according to the normalized consensus hydrophobicityscale of Eisenberg, 1984, J. Mol. Biol. 179:125-142. Hydrophobic aminoacid residues include, but are not limited to, Ile (I), Phe (F), Val(V), Leu (L), Trp (W), Met (M), Ala (A), Gly (G), Tyr (Y), β-Ala, Nip,t-BuA, t-BuG, Melle, PhG, ChA, Nle, NaI, Phe(4-C1), Phe(2-F), Phe(3-F),Phe(4-F), Tic, Thi, MeVal, hPhe, hPro, 3-aminopropionic acid, 4aminobutryic acid, Inp, Aib, Aha, Ava, MeGly, D-Pro, D-Ile, D-Phe,D-Val, D-Leu, D-Trp, D-Met, D-Ala, D-Tyr, D-1-Ala, D-Nip, D-t-BuA,D-t-BuG, D-Melle, D-PhG, D-ChA, D-Nle, D-NaI, D-Phe(4-Cl), D-Phe(2-F),D-Phe(3-F), D-Phe(4-F), D-Tic, D-Thi, D-MeVal, D-hPhe, and D-hPro. Otherhydrophobic amino acids include, but are not limited to, C₁₋₄ lateralchain analogs having the following formulas:

wherein n is an integer from 1 to 4. In one embodiment, the hydrophobicamino acid residue is an L-amino acid residue. In another embodiment,the hydrophobic amino acid residue is a D-amino acid residue. In anotherembodiment, the hydrophobic amino acid residue is an achiral amino acidresidue.

“Polar amino acid residue,” as used herein unless otherwise defined,refers to a hydrophilic amino acid residue having a side chain that isuncharged at physiological pH, but which has at least one bond in whichthe pair of electrons shared in common by two atoms is held more closelyby one of the atoms. Polar amino acid residues include, but are notlimited to, Asn (N), Gln (O), Ser (S), Thr (T), Cit, Pen, MSO, AcLys,hCys, hSer, Hyp, D-Asn, D-Gln, D-Ser, D-Thr, D-Cit, D-Pen, D-MSO,D-AcLys, D-hCys, D-hSer, and D-Hyp. Other polar amino acids include, butare not limited to, C₁₋₄ lateral chain analogs having the followingformulas:,

wherein n is an integer from 1 to 4. In one embodiment, the polar aminoacid residue is an L-amino acid residue. In another embodiment, thepolar amino acid residue is a D-amino acid residue. In anotherembodiment, the polar amino acid residue is an achiral amino acidresidue.

“Acidic amino acid residue,” as used herein unless otherwise defined,refers to a hydrophilic amino acid residue having a side chain pK valueof less than 7. Acidic amino acid residues typically have negativelycharged side chains at physiological pH due to loss of a hydrogen ion.Acidic amino acid residues include, but are not limited to, Glu (E), Asp(D), D-Glu, and D-Asp. Other acidic amino acids include, but are notlimited to, C₁₋₄ lateral chain analogs having the following formula:

wherein n is an integer from 1 to 4. In one embodiment, the acidic aminoacid residue is an L-amino acid residue. In another embodiment, theacidic amino acid residue is a D-amino acid residue. In anotherembodiment, the acidic amino acid residue is an achiral amino acidresidue.

“Basic amino acid residue,” as used herein unless otherwise defined,refers to a hydrophilic amino acid residue having a side chain pK valueof greater than 7. Basic amino acid residues typically have positivelycharged side chains at physiological pH due to association with ahydronium ion. Basic amino acid residues include, but are not limitedto, His (H), Arg (R), Lys (K), Dpr, Orn, hArg, Dbu, Dab, Phe(p-NH₂),D-His, D-Arg, D-Lys, D-Dpr, D-Orn, D-hArg, D-Dbu, D-Dab, andD-Phe(p-NH₂). Other basic amino acid residues include, but are notlimited to, C₁₋₄ lateral chain analogs having the following formulas:

wherein n is an integer from 1 to 4. In one embodiment, the basic aminoacid residue is an L-amino acid residue. In another embodiment, thebasic amino acid residue is a D-amino acid residue. In anotherembodiment, the basic amino acid residue is an achiral amino acidresidue.

“Nonpolar amino acid residue,” as used herein unless otherwise defined,refers to a hydrophobic amino acid residue having a side chain that isuncharged at physiological pH and which has bonds in which the pair ofelectrons shared in common by two atoms is held substantially equally byeach of the two atoms (i.e., the side chain is not polar). Non-polaramino acid residues include, but are not limited to, Leu (L), Val (V),Ile (I), Met (M), Gly (G), Ala (A), Pro (P), azPro, Pip, azPip, β-Ala,Nip, t-BuG, Melle, ChA, Nle, MeVal, hPro, 3-aminopropionic acid,4-aminobutyric acid, Inp, Aib, Aha, Ava, MeGly, D-Leu, D-Val, D-Ile,D-Met, D-Ala, D-Pro, D-β-Ala, D-Inp, D-t-BuG, D-Melle, D-ChA, D-Nle,D-MeVal, D-Nip, D-Pip, and D-hPro. Other non-polar amino acid residuesinclude, but are not limited to, C₁₋₄ lateral chain analogs having thefollowing formulas:

wherein n is an integer from 1 to 4. In one embodiment, the non-polaramino acid residue is an L-amino acid residue. In another embodiment,the non-polar amino acid residue is a D-amino acid residue. In anotherembodiment, the non-polar amino acid residue is an achiral amino acidresidue.

“Aromatic amino acid residue,” as used herein unless otherwise defined,refers to a hydrophobic amino acid residue with a side chain having atleast one aromatic or heteroaromatic ring. The aromatic orheteroaromatic ring can contain one or more substituents such as —OH,—SH, —CN, —F, —Cl, —Br, —I, —NO₂, —NO, —NH₂, —NHR, —NRR, —C(O)R,—C(O)OH, —C(O)OR, —C(O)NH₂, —C(O)NHR, —C(O)NRR where each R isindependently (C₁-C₆) alkyl, substituted (C₁-C₆) alkyl, 5-26-memberedaryl, and substituted 5-26-membered aryl. Aromatic amino acid residuesinclude, but are not limited to, Phe (F), Tyr (Y), Trp (W), PhG, NaI,Phe(4-CO, Phe(2-F), Phe(3-F), Phe(4-F), Tic, Thi, hPhe, D-Phe, D-Tyr andD-Trp, D-PhG, D-NaI, D-Phe(4-Cl), D-Phe(2-F), D-Phe(3-F), D-Phe(4-F),D-Tic, D-Thi, and D-hPhe. Other aromatic amino acid residues include,but are not limited to, C₁₋₄ lateral chain analogs having the followingformulas:

wherein n is an integer from 1 to 4. In one embodiment, the aromaticamino acid residue is an L-amino acid residue. In another embodiment,the aromatic amino acid residue is a D-amino acid residue. In anotherembodiment, the aromatic amino acid residue is an achiral amino acidresidue.

The classifications of the genetically encoded and non-geneticallyencoded amino acid residues according to the categories defined aboveare summarized in the table below. It is to be understood that thefollowing table is included for illustrative purposes only and does notpurport to be an exhaustive list of amino acid residues that can be usedin the ApoA-I Mimics described herein. Other amino acid residues notspecifically disclosed herein can be readily categorized based on theirobserved physical and chemical properties in view of the definitionsprovided herein. Some classifications of amino acid residues areincluded in Table 2 below.

TABLE 2 Classifications of Some Amino Acid Residues ClassificationGenetically Encoded Non-Genetically Encoded Hydrophobic Aromatic F, Y, WPhG, Nal, Thi, Tic, Phe(4- Cl), Phe(2-F), Phe(3-F), Phe(4-F), hPheNonpolar L, V, I, M, G, A, P -Ala, t-BuA, t-BuG, Melle, Nle, MeVal, ChA,MeGly, Aib, Nip, hPro, Aliphatic A, V, L, I, P -Ala, Aib, t-BuA, t-BuG,Melle, ChA, Nle, MeVal, Nip, hPro, Inp, azPro, Pip, Hydrophilic AcidicD, E Basic H, K, R Dpr, Orn, hArg, Phe(p-NH₂), Dbu, Dab, hArg Polar C,Q, N, S, T Cit, Pen, AcLys, MSO, bAla, hSer, hCys, hSer, HypHelix-Breaking P, G MeGly, L-amino acids (in D-peptides), D-Pro andother D-amino acids (in L-peptides),

As will be appreciated by those of skill in the art, the above-definedcategories are not mutually exclusive. Thus, amino acid residues havingside chains exhibiting two or more physical-chemical properties can beincluded in multiple categories. For example, amino acid side chainshaving aromatic moieties that are further substituted with polarsubstituents, such as Tyr (Y) or its corresponding D-enantiomer, canexhibit both aromatic hydrophobic properties and polar or hydrophilicproperties, and can therefore be included in both the aromatic and polarcategories. The appropriate categorization of any amino acid residuewill be apparent to those of skill in the art, especially in view of thedisclosure provided herein.

In addition, the amino acid residue Cys (C) or its correspondingD-enantiomer can form disulfide bridges with other Cys (C) residues ortheir corresponding D-enantiomers or with other sulfanyl-containingamino acids. The ability of Cys (C) residues (and other amino acids with—SH containing side chains) to exist in a peptide in either the reducedfree —SH or oxidized disulfide-bridged form affects whether Cys (C)residues or their corresponding D-enantiomers contribute net hydrophobicor hydrophilic character to a peptide. While Cys (C) or itscorresponding D-enantiomer exhibits a hydrophobicity of 0.29 accordingto the normalized consensus scale of Eisenberg (Eisenberg, 1984, supra),it is to be understood that for purposes of the present invention Cys(C) and its corresponding D-enantiomer are categorized as polarhydrophilic amino acids, notwithstanding the general classificationsdefined above.

II ApoA-I Mimics

A. Peptides of Formula I

In one embodiment, the invention provides 15- to 29-residue peptideshaving the following Formula IR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue or an achiral, D-,or L-basic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to eight of residues X² to X²² are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 22- to 29-residue peptideshaving the following Formula IR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is an achiral, D-, or L-basic amino acid residue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 15- to 21-residue peptideshaving the following Formula IR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is an achiral, D-, or L-basic amino acid residue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein one to eight of residues X² to X²² are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the peptide of Formula I or pharmaceuticallyacceptable salt thereof is 22 amino acid residues in length and X¹ isabsent.

The following embodiments relate to the ApoA-1 Mimics of Formula I,unless otherwise specified.

In one embodiment, X² and X⁴ are both Lys, Orn, D-Lys, or D-Orn. Inanother embodiment, X⁵ is Gln, Lys, D-Gln, or D-Lys. In anotherembodiment, X⁹ is an acidic amino acid residue. In another embodiment,X¹² is Glu, Asn, Gln, Arg, D-Glu, D-Asn, D-Gln, or D-Arg. In anotherembodiment, X¹³ is Glu, Asn, Gln, Arg, D-Glu, D-Asn, D-Gln, or D-Arg. Inanother embodiment, X¹⁶ is an acidic amino acid residue. In anotherembodiment, X¹⁷ is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn. In anotherembodiment, X²¹ is Leu or D-Leu. In another embodiment, X²² is Ala, Val,Leu, D-Ala, D-Val, or D-Leu.

In another embodiment, X¹ is absent; X¹³ is an acidic amino acidresidue, Arg, or D-Arg; X¹⁴ is a basic amino acid residue, Asn, Glu,D-Asn, or D-Glu; and X² to X¹² and X¹⁵ to X²³ are as defined above inFormula I.

In another embodiment, X¹ is absent; X² is Lys, Orn, D-Lys, or D-Orn; X³is Leu or D-Leu; X⁴ is Lys, Orn, D-Lys, or D-Orn; X⁵ is Lys, Orn, Gln,Asn, D-Lys, D-Orn, D-Gln, or D-Asn; X⁶ is Lys, Orn, Gln, Asn, D-Lys,D-Orn, D-Gln, or D-Asn; X⁷ is Leu, Gly, NaI, D-Leu, or D-NaI; X⁸ is Ala,Trp, Gly, Leu, Phe, NaI, D-Ala, D-Trp, D-Leu, D-Phe, or D-NaI; X⁹ isAsp, Glu, Gln, Lys, D-Asp, D-Glu, D-Gln, or D-Lys; X¹¹ is Leu, Gly,D-Leu, or Aib; X¹² is Asp, Glu, Asn, D-Asp, D-Glu, or D-Asn; X¹³ is Asn,Gln, Glu, Arg, D-Asn, D-Gln, D-Glu, or D-Arg; X¹⁶ is Asp, Arg, Glu,D-Asp, D-Arg, or D-Glu; X¹⁷ is Lys, Arg, Orn, Asn, Glu, D-Lys, D-Arg,D-Orn, D-Asn, or D-Glu; X²⁰ is Asp, Glu, D-Asp, or D-Glu; and/or X²² isAla, Val, Leu, D-Ala, D-Val, or D-Leu; and X¹⁰, X¹⁴, X¹⁵, X¹⁹, X²¹, andX² are as defined above in Formula I.

In another embodiment, X¹ is absent; X⁹ is Glu or D-Glu; X¹² is Glu orD-Glu; X¹³ is Asn, Glu, D-Asn, or D-Glu; X¹⁴ is Leu or D-Leu; X¹⁵ is Leuor D-Leu; X¹⁶ is Glu or D-Glu; X¹⁷ is Arg, Lys, D-Arg, or D-Lys; X¹⁸ isPhe or D-Phe; X¹⁹ is Leu or D-Leu; X²¹ is Leu or D-Leu; and/or X²² isVal or D-Val; and X² to X⁸, X¹⁰, X¹¹, X²⁰, and X²³ are as defined abovein Formula I.

In another embodiment, X¹ is absent; X² is Lys, Orn, D-Lys, or D-Orn; X³is Leu or D-Leu; X⁴ is Lys, Orn, D-Lys, or D-Orn; X⁵ is Lys, Orn, Gln,Asn, D-Lys, D-Orn, D-Gln, or D-Asn; X⁶ is Lys, Orn, Gln, Asn, D-Lys,D-Orn, D-Gln, or D-Asn; X⁷ is Leu, Gly, NaI, D-Leu, or D-NaI; X⁸ is Ala,Trp, Gly, Leu, Phe, NaI, D-Ala, D-Trp, D-Leu, D-Phe, or D-NaI; X⁹ is Gluor D-Glu; X¹¹ is Leu, D-Leu, Gly, or Aib; X¹² is Glu or D-Glu; X¹³ isAsn, Glu, D-Asn, or D-Glu; X¹⁴ is Leu or D-Leu; X¹⁵ is Leu or D-Leu; X¹⁶is Glu or D-Glu; X¹⁷ is Arg, Lys, D-Arg, or D-Lys; X¹⁸ is Phe or D-Phe;X¹⁹ is Leu or D-Leu; X²⁰ is Asp, Glu, D-Asp, or D-Glu; X²¹ is Leu orD-Leu; and/or X²² is Val or D-Val; and X¹⁰ and X²³ are as defined abovein Formula I.

In another embodiment, X¹ is absent, only one of X⁵ and X⁶ is a basicamino acid residue, and the other of X⁵ and X⁶ is Gln, Asn, D-Gln, orD-Asn.

In another embodiment, Y¹ or Y² is absent or is a sequence having fromone to seven amino acid residues. In another embodiment, one or more ofthe amino acid residues of the amino acid sequence is an acidic aminoacid residue. In another embodiment, one or more of the amino acidresidues of the amino acid sequence is a basic amino acid residue.

In another embodiment, one of X⁵ and X⁶ is Lys, Orn, D-Lys, or D-Orn,and the other of X⁵ and X⁶ is Gln, Asn, D-Gln, or D-Asn.

In another embodiment, each chiral amino acid residue is an L-amino acidresidue.

In another embodiment, each chiral amino acid residue is a D-amino acidresidue.

In another embodiment, X¹ is absent; one of X⁷, X⁸, X¹⁰, X¹¹, X¹⁴ andX¹⁵ is Gly; and X¹ to X⁶, X⁹, X¹², X¹³, and X¹⁶ to X²³ are other thanGly.

In another embodiment, X¹ is absent; X¹¹ is Gly; and each of X⁷, X⁸,X¹⁰, X¹⁴, and X¹⁵ is other than Gly.

In another embodiment, X¹ is absent; X² is Lys, Orn, D-Lys, or D-Orn; X³is Leu or D-Leu; X⁴ is Lys, Orn, D-Lys, or D-Orn; X⁵ is Gln or D-Gln; X⁶is Lys, Orn, D-Lys, or D-Orn; X⁷ is Leu, NaI, D-Leu, or D-NaI; X⁸ isAla, Trp, D-Ala, or D-Trp; X⁹ is Glu or D-Glu; X¹⁰ is Leu or D-Leu; X¹¹is Gly; X¹² is Glu or D-Glu; X¹³ is Asn or D-Asn; X¹⁴ is Leu, Trp,D-Leu, or D-Trp; X¹⁵ is Leu or D-Leu; X¹⁶ is Glu or D-Glu; X¹⁷ is Arg orD-Arg; X¹⁸ is Phe or D-Phe; X¹⁹ is Leu, Phe, D-Leu, or D-Phe; X²⁰ isAsp, Glu, D-Asp, or D-Glu; X²¹ is Leu or D-Leu; X²² is Val or D-Val; andX²³ is Inp. In one embodiment, the peptide of Formula I is a peptide setforth in Table 3 below:

TABLE 3 Peptide 2Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 2) Peptide 3Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 3) Peptide 4Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 4) Peptide 5Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 5) Peptide 6Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 6) Peptide 7Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 7) Peptide 8Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp (SEQ. ID. NO. 8) Peptide 9Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 9) Peptide 94Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 94) Peptide 95Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 95) Peptide 96Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 96) Peptide 97Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 97) Peptide 98Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 98) Peptide 99Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 99) Peptide 100Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip (SEQ. ID. NO. 100) Peptide 101Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 101) Peptide 214Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 214) Peptide 215Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 215) Peptide 216Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 216) Peptide 217Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 217) Peptide 218Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 218) Peptide 219Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 219) Peptide 220Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPro (SEQ. ID. NO. 220) Peptide 221Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 221) Peptide 306Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 306) Peptide 307Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 307) Peptide 308Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 308) Peptide 309Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 309) Peptide 310Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 310) Peptide 311Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 311) Peptide 312Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Pip (SEQ. ID. NO. 312) Peptide 313Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 313) Peptide 398Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 398) Peptide 399Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 399) Peptide 400Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 400) Peptide 401Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 401) Peptide 402Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 402) Peptide 403Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 403) Peptide 404Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPip (SEQ. ID. NO. 404) Peptide 405Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 405)or a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; X¹⁵ is Gly; and each of X⁷, X⁸,X¹⁰, X¹¹, and X¹⁴ is other than Gly. In one embodiment, the peptide ofFormula I is:

Peptide 10 (SEQ. ID. NO. 10)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or Peptide 102(SEQ. ID. NO. 102) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip Peptide 222 (SEQ. ID. NO. 222)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro Peptide 314 (SEQ. ID. NO. 314)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip Peptide 406 (SEQ. ID. NO. 406)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPipor a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; X¹⁴ is Gly; and each of X⁷, X⁸,X¹⁰, X¹¹, and X¹⁵ is other than Gly. In one embodiment, the peptide ofFormula I is:

Peptide 11 (SEQ. ID. NO. 11)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or Peptide 103(SEQ. ID. NO. 103) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip Peptide 223 (SEQ. ID. NO. 223)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro Peptide 315 (SEQ. ID. NO. 315)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip Peptide 407 (SEQ. ID. NO. 407)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPipor a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; X¹⁰ is Gly; and each of X⁷, X⁸,X¹¹, X¹⁴, and X¹⁵ is other than Gly. In one embodiment, the peptide ofFormula I is:

Peptide 12 (SEQ. ID. NO. 12)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or Peptide 104(SEQ. ID. NO. 104) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip Peptide 224 (SEQ. ID. NO. 224)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro Peptide 316 (SEQ. ID. NO. 316)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip Peptide 408 (SEQ. ID. NO. 408)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPipor a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; X⁸ is Gly; and each of X⁷, X¹⁰,X¹¹, X¹⁴, and X¹⁵ is other than Gly. In one embodiment, the peptide ofFormula I is:

Peptide 13 (SEQ. ID. NO. 13)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or Peptide 105(SEQ. ID. NO. 105) Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip Peptide 225 (SEQ. ID. NO. 225)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro Peptide 317 (SEQ. ID. NO. 317)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip Peptide 409 (SEQ. ID. NO. 409)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPipor a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; X⁷ is Gly; and each of X⁸, X¹⁰,X¹¹, X¹⁴, and X¹⁵ is other than Gly. In one embodiment, the peptide ofFormula I is:

Peptide 14 (SEQ. ID. NO. 14)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or Peptide 106(SEQ. ID. NO. 106) Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip Peptide 226 (SEQ. ID. NO. 226)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro Peptide 318 (SEQ. ID. NO. 318)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip Peptide 410 (SEQ. ID. NO. 410)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPipor a pharmaceutically acceptable salt thereof.

In another embodiment, X¹ is absent; and each of X⁷, X⁸, X¹⁰, X¹¹, X¹⁴,and X¹⁵ is other than Gly.

In another embodiment, X¹ is absent; X² is Lys, Orn, D-Lys, or D-Orn; X³is Leu or D-Leu; X⁴ is Lys, Orn, D-Lys, or D-Orn; one of X⁵ or X⁶ is Glnor D-Gln and the other of X⁵ or X⁶ is Lys, Orn, D-Lys, or D-Orn; X⁷ isLeu, NaI, D-Leu, or D-NaI; X⁸ is Ala, Leu, Trp, NaI, D-Ala, D-Leu,D-Trp, or D-NaI; X⁹ is Glu or D-Glu; X¹⁰ is Leu, Trp, NaI, D-Leu, D-Trp,or D-NaI; X¹¹ is Leu, D-Leu or Aib; X¹² is Glu or D-Glu; X¹³ is Asn,Gln, D-Asn, or D-Gln; X¹⁴ is Leu, Trp, D-Leu, or D-Trp; X¹⁵ is Leu orD-Leu; X¹⁶ is Glu or D-Glu; X¹⁷ is Arg, Lys, D-Arg, or D-Lys; X¹⁸ isLeu, Phe, D-Leu, or D-Phe; X¹⁹ is Leu, Phe, D-Leu, or D-Phe; X²⁰ is Asp,Glu, D-Asp, or D-Glu; X²¹ is Leu or D-Leu; X²² is Val, Leu, D-Val, orD-Leu; and X²³ is Inp.

In another embodiment, X¹ is absent; X² is Lys or D-Lys; X³ is Leu orD-Leu; X⁴ is Lys or D-Lys; X⁵ is Glu or D-Glu; X⁶ is Lys or D-Lys; X⁷ isLeu or D-Leu; X⁸ is Ala or D-Ala; X⁹ is Glu or D-Glu; X¹⁰ is Leu orD-Leu; X¹¹ is Leu or D-Leu; X¹² is Glu or D-Glu; X¹³ is Asn or D-Asn;X¹⁴ is Leu or D-Leu; X¹⁵ is Leu or D-Leu; X¹⁶ is Glu or D-Glu; X¹⁷ isArg or D-Arg; X¹⁸ is Phe or D-Phe; X¹⁹ is Leu or D-Leu; X²⁰ is Asp orD-Asp; X²¹ is Leu or D-Leu; X²² is Val or D-Val; and/or X²³ is Inp.

In another embodiment, X³ is other than Lys or D-Lys; X⁹ is other thanTrp or D-Trp; X¹¹ is other than Glu, Trp, D-Glu, or D-Trp; X¹² is otherthan Trp, Leu, D-Trp, or D-Leu; X¹³ is other than Trp or D-Trp; X¹⁵ isother than Lys, Trp, D-Lys, or D-Trp; X¹⁶ is other than Trp or D-Trp;X¹⁷ is other than Trp, Leu, D-Trp, or D-Leu; X¹⁸ is other than Trp orD-Trp; X¹⁹ is other than Lys, Glu, Trp, NaI, D-Lys, D-Glu, D-Trp, orD-NaI; and/or X²² is other than Val or D-Val.

In another embodiment, the peptide of Formula I is one of the peptidesset forth in Table 4 below:

TABLE 4 Peptide 15Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 15) Peptide 16Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 16) Peptide 17Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 17) Peptide 18Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 18) Peptide 19Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 19) Peptide 20Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 20) Peptide 21Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 21) Peptide 22Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 22) Peptide 23Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 23) Peptide 24Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 24) Peptide 25Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 25) Peptide 26Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Inp (SEQ. ID. NO. 26) Peptide 27Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 27) Peptide 28Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp (SEQ. ID. NO. 28) Peptide 29Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 29) Peptide 30Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 30) Peptide 31Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 31) Peptide 32Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 32) Peptide 33Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 33) Peptide 34Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 34) Peptide 35Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 35) Peptide 36Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 36) Peptide 37Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 37) Peptide 38Lys-Leu-Lys-Lys-Asn-Leu-Ala-Gln-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 38) Peptide 39Lys-Leu-Lys-Gln-Asn-Leu-Ala-Lys-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 39) Peptide 40Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp (SEQ. ID. NO. 40) Peptide 107Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 107) Peptide 108Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 108) Peptide 109Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 109) Peptide 110Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 110) Peptide 111Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 111) Peptide 112Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 112) Peptide 113Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 113) Peptide 114Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 114) Peptide 115Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 115) Peptide 116Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 116) Peptide 117Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 117) Peptide 118Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Nip (SEQ. ID. NO. 118) Peptide 119Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 119) Peptide 120Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip (SEQ. ID. NO. 120) Peptide 121Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 121) Peptide 122Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 122) Peptide 123Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 123) Peptide 124Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 124) Peptide 125Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 125) Peptide 126Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 126) Peptide 127Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 127) Peptide 128Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 128) Peptide 129Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 129) Peptide 130Lys-Leu-Lys-Lys-Asn-Leu-Ala-Gln-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 130) Peptide 131Lys-Leu-Lys-Gln-Asn-Leu-Ala-Lys-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 131) Peptide 132Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip (SEQ. ID. NO. 132) Peptide 227Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 227) Peptide 228Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 228) Peptide 229Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 229) Peptide 230Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 230) Peptide 231Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 231) Peptide 232Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 232) Peptide 233Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 233) Peptide 234Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 234) Peptide 235Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 235) Peptide 236Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 236) Peptide 237Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 237) Peptide 238Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPro (SEQ. ID. NO. 238) Peptide 239Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 239) Peptide 240Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPro (SEQ. ID. NO. 240) Peptide 241Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 241) Peptide 242Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 242) Peptide 243Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 243) Peptide 244Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 244) Peptide 245Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 245) Peptide 246Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 246) Peptide 247Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 247) Peptide 248Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 248) Peptide 249Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 249) Peptide 250Lys-Leu-Lys-Lys-Asn-Leu-Ala-Gln-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 250) Peptide 251Lys-Leu-Lys-Gln-Asn-Leu-Ala-Lys-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 251) Peptide 252Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro (SEQ. ID. NO. 252) Peptide 319Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 319) Peptide 320Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 320) Peptide 321Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 321) Peptide 322Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 322) Peptide 323Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 323) Peptide 324Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 324) Peptide 325Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 325) Peptide 326Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 326) Peptide 327Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 327) Peptide 328Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 328) Peptide 329Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 329) Peptide 330Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Pip (SEQ. ID. NO. 330) Peptide 331Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 331) Peptide 332Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Pip (SEQ. ID. NO. 332) Peptide 333Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 333) Peptide 334Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 334) Peptide 335Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 335) Peptide 336Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 336) Peptide 337Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 337) Peptide 338Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 338) Peptide 339Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 339) Peptide 340Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 340) Peptide 341Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 341) Peptide 342Lys-Leu-Lys-Lys-Asn-Leu-Ala-Gln-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 342) Peptide 343Lys-Leu-Lys-Gln-Asn-Leu-Ala-Lys-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 343) Peptide 344Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip (SEQ. ID. NO. 344) Peptide 411Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 411) Peptide 412Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 412) Peptide 413Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 413) Peptide 414Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 414) Peptide 415Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 415) Peptide 416Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 416) Peptide 417Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 417) Peptide 418Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 418) Peptide 419Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-rg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 419) Peptide 420Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 420) Peptide 421Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 421) Peptide 422Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPip (SEQ. ID. NO. 422) Peptide 423Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 423) Peptide 424Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPip (SEQ. ID. NO. 424) Peptide 425Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 425) Peptide 426Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 426) Peptide 427Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 427) Peptide 428Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 428) Peptide 429Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 429) Peptide 430Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 430) Peptide 431Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 431) Peptide 432Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 432) Peptide 433Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Asn-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 433) Peptide 434Lys-Leu-Lys-Lys-Asn-Leu-Ala-Gln-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 434) Peptide 435Lys-Leu-Lys-Gln-Asn-Leu-Ala-Lys-Leu-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 435) Peptide 436Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip (SEQ. ID. NO. 436)or a pharmaceutically acceptable salt thereof.

B. Peptides of Formula II

In one embodiment, the invention encompasses 14- to 22-residue peptideshaving the following Formula IIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—Y²—R²,  FormulaIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is an achiral, D-, or L-basic amino acid residue;

X² is Leu or D-Leu;

X³ is an achiral, D-, or L-basic amino acid residue;

X⁴ is Gln, Asn, D-Gln, or D-Asn;

X⁵ is Leu, D-Leu, or an achiral, D-, or L-basic amino acid amino acidresidue;

X⁶ is Leu, Trp, Phe, D-Leu, D-Trp, or D-Phe;

X⁷ is an achiral, D-, or L-acidic amino acid residue;

X⁸ is Asn, D-Asn, or an achiral, D-, or L-acidic amino acid residue;

X⁹ is Leu, Trp, D-Leu, or D-Trp;

X¹⁰ is Leu, Trp, D-Leu, or D-Trp;

X¹¹ is an achiral, D-, or L-acidic amino acid residue;

X¹² is an achiral, D-, or L-basic amino acid residue;

X¹³ is Leu, Phe, D-Leu, or D-Phe;

X¹⁴ is Leu, Phe, D-Leu, or D-Phe;

X¹⁵ is an achiral, D-, or L-acidic amino acid residue;

X¹⁶ is Leu or D-Leu;

X¹⁷ is an achiral, D-, or L-aliphatic amino acid residue;

X¹⁸ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 4 residues;

Y² is absent or an amino acid sequence having from 1 to 4 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to eight of residues X¹ to X¹⁷ are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention encompasses 15- to 22-residuepeptides having the following Formula IIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—Y²—R²,  FormulaIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is an achiral, D-, or L-basic amino acid residue;

X² is Leu or D-Leu;

X³ is an achiral, D-, or L-basic amino acid residue;

X⁴ is Gln, Asn, D-Gln, or D-Asn;

X⁵ is Leu, D-Leu, or an achiral, D-, or L-basic amino acid amino acidresidue;

X⁶ is Leu, Trp, Phe, D-Leu, D-Trp, or D-Phe;

X⁷ is an achiral, D-, or L-acidic amino acid residue;

X⁸ is Asn, D-Asn, or an achiral, D-, or L-acidic amino acid residue;

X⁹ is Leu, Trp, D-Leu, or D-Trp;

X¹⁰ is Leu, Trp, D-Leu, or D-Trp;

X¹¹ is an achiral, D-, or L-acidic amino acid residue;

X¹² is an achiral, D-, or L-basic amino acid residue;

X¹³ is Leu, Phe, D-Leu, or D-Phe;

X¹⁴ is Leu, Phe, D-Leu, or D-Phe;

X¹⁵ is an achiral, D-, or L-acidic amino acid residue;

X¹⁶ is Leu or D-Leu;

X¹⁷ is an achiral, D-, or L-aliphatic amino acid residue;

X¹⁸ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 4 residues;

Y² is absent;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to three of residues X¹ to X¹⁷ are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention encompasses 14-residue peptideshaving the following Formula IIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—Y²—R²,  FormulaIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is an achiral, D-, or L-basic amino acid residue;

X² is Leu or D-Leu;

X³ is an achiral, D-, or L-basic amino acid residue;

X⁴ is Gln, Asn, D-Gln, or D-Asn;

X⁵ is Leu, D-Leu, or an achiral, D-, or L-basic amino acid amino acidresidue;

X⁶ is Leu, Trp, Phe, D-Leu, D-Trp, or D-Phe;

X⁷ is an achiral, D-, or L-acidic amino acid residue;

X⁸ is Asn, D-Asn, or an achiral, D-, or L-acidic amino acid residue;

X⁹ is Leu, Trp, D-Leu, or D-Trp;

X¹⁰ is Leu, Trp, D-Leu, or D-Trp;

X¹¹ is an achiral, D-, or L-acidic amino acid residue;

X¹² is an achiral, D-, or L-basic amino acid residue;

X¹³ is Leu, Phe, D-Leu, or D-Phe;

X¹⁴ is Leu, Phe, D-Leu, or D-Phe;

X¹⁵ is an achiral, D-, or L-acidic amino acid residue;

X¹⁶ is Leu or D-Leu;

X¹⁷ is an achiral, D-, or L-aliphatic amino acid residue;

X¹⁸ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 4 residues;

Y² is absent;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein four to eight of residues X¹ to X¹⁷ are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In one embodiment, the peptide of Formula II is an 18-residue peptide.

In one embodiment, the peptide of Formula II is a peptide set forth inTable 5 below.

TABLE 5 Peptide 51Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 51) Peptide 53Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 53) Peptide 54Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 54) Peptide 55Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp(SEQ. ID. NO. 55) Peptide 56Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 56) Peptide 58Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 58) Peptide 143Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 143) Peptide 145Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 145) Peptide 146Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 146) Peptide 147Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip(SEQ. ID. NO. 147) Peptide 148Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 148) Peptide 150Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 150) Peptide 263Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro(SEQ. ID. NO. 263) Peptide 265Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro(SEQ. ID. NO. 265) Peptide 266Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro(SEQ. ID. NO. 266) Peptide 267Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPro(SEQ. ID. NO. 267) Peptide 268Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro(SEQ. ID. NO. 268) Peptide 270Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro(SEQ. ID. NO. 270) Peptide 355Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 355) Peptide 357Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-L eu-Leu-Glu-Arg-Phe-Leu-Asp-L eu-Val-Pip(SEQ. ID. NO. 357) Peptide 358Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 358) Peptide 359Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-L eu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Pip(SEQ. ID. NO. 359) Peptide 360Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 360) Peptide 362Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 362) Peptide 447Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip(SEQ. ID. NO. 447) Peptide 449Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip(SEQ. ID. NO. 449) Peptide 450Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip(SEQ. ID. NO. 450) Peptide 451Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPip(SEQ. ID. NO. 451) Peptide 452Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip(SEQ. ID. NO. 452) Peptide 454Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip(SEQ. ID. NO. 454)or a pharmaceutically acceptable salt thereof.

C. Peptides of Formula III

In one embodiment, the invention provides 15- to 29-residue peptideshaving the following Formula IIIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIIIor a pharmaceutically acceptable salt thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue or an achiral, D-,or L-basic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to eight of residues X² to X²² are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 22- to 29-residue peptideshaving the following Formula IIIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral D-, or L-basic amino acidresidue;

X⁶ is an achiral, D-, or L-basic amino acid residue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the invention provides 15- to 21-residue peptideshaving the following Formula IIIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is an achiral, D-, or L-aliphatic amino acid residue;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or an achiral, D-, or L-basic amino acidresidue;

X⁶ is an achiral, D-, or L-basic amino acid residue;

X⁷ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁸ is an achiral, D-, or L-hydrophobic amino acid residue;

X⁹ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an achiral, D-, or L-aliphatic amino acid residue;

X¹² is an achiral, D-, or L-hydrophilic amino acid residue;

X¹³ is an achiral, D-, or L-hydrophilic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an achiral, D-, or L-acidic amino acid residue;

X¹⁷ is an achiral, D-, or L-hydrophibic amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is an Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an achiral, D-, or L-acidic amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein one to eight of residues X² to X²² are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

In another embodiment, the peptide of Formula III is 22 amino acidresidues in length and X¹ is absent.

In one embodiment, the peptide of Formula III is a peptide set forth inTable 6 below.

TABLE 6 Peptide 186Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Phe-Val-Inp (SEQ. ID. NO. 186) Peptide 187Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Gly-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 187) Peptide 188Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Trp-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 188) Peptide 189Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 189) Peptide 190Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 190) Peptide 191Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 191) Peptide 192Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 192) Peptide 193Lys-Leu-Lys-Lys-Gln-Leu-Leu-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 193) Peptide 194Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Gly-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 194) Peptide 195Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 195) Peptide 196Orn-Leu-Orn-Orn-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 196) Peptide 197Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 197) Peptide 198Lys-Leu-Lys-Lys-Asn-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 198) Peptide 199Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Asp-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 199) Peptide 200Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Phe-Val-Nip (SEQ. ID. NO. 200) Peptide 201Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Gly-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 201) Peptide 202Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Trp-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 202) Peptide 203Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 203) Peptide 204Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 204) Peptide 205Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 205) Peptide 206Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 206) Peptide 207Lys-Leu-Lys-Lys-Gln-Leu-Leu-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 207) Peptide 208Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Gly-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 208) Peptide 209Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 209) Peptide 210Orn-Leu-Orn-Orn-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 210) Peptide 211Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 211) Peptide 212Lys-Leu-Lys-Lys-Asn-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 212) Peptide 213Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Asp-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 213) Peptide 490Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Phe-Val-azPro (SEQ. ID. NO. 490) Peptide 491Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Gly-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 491) Peptide 492Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Trp-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 492) Peptide 493Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 493) Peptide 494Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 494) Peptide 495Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 495) Peptide 496Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 496) Peptide 497Lys-Leu-Lys-Lys-Gln-Leu-Leu-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 497) Peptide 498Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Gly-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 498) Peptide 499Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 499) Peptide 500Orn-Leu-Orn-Orn-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 500) Peptide 501Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 501) Peptide 502Lys-Leu-Lys-Lys-Asn-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 502) Peptide 503Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Asp-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 503) Peptide 504Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Phe-Val-Pip (SEQ. ID. NO. 504) Peptide 505Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Gly-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 505) Peptide 506Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Trp-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 506) Peptide 507Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 507) Peptide 508Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 508) Peptide 509Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 509) Peptide 510Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 510) Peptide 511Lys-Leu-Lys-Lys-Gln-Leu-Leu-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 511) Peptide 512Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Gly-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 512) Peptide 513Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 513) Peptide 514Orn-Leu-Orn-Orn-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 514) Peptide 515Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 515) Peptide 516Lys-Leu-Lys-Lys-Asn-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 516) Peptide 517Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Asp-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 517) Peptide 518Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Phe-Val-azPip (SEQ. ID. NO. 518) Peptide 519Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Gly-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 519) Peptide 520Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Trp-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 520) Peptide 521Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 521) Peptide 522Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 522) Peptide 523Lys-Leu-Lys-Lys-Gln-Leu-Trp-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 523) Peptide 524Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 524) Peptide 525Lys-Leu-Lys-Lys-Gln-Leu-Leu-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 525) Peptide 526Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Gly-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 526) Peptide 527Lys-Leu-Lys-Lys-Gln-Trp-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Leu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 527) Peptide 528Orn-Leu-Orn-Orn-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 528) Peptide 529Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 529) Peptide 530Lys-Leu-Lys-Lys-Asn-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 530) Peptide 531Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Asp-Leu-Leu-Asn-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 531)or a pharmaceutically acceptable salt thereof.

In other embodiments, the present invention includes ApoA-I Mimicswherein one or more of its amide linkages is optionally replaced with alinkage other than amide, including, but not limited to, a substitutedamide or an isostere of amide. Thus, while the various X¹ to X²³, Y¹ andY² residues within Formulas I, II, and III are described in terms ofamino acids, in particular embodiments of the invention, a non-amidelinkage is present in place of one or more amide linkages.

In another embodiment, the nitrogen atom of one or more of the ApoA-IMimics' amide linkages is substituted, such that the substituted amidelinkage has the formula —C(O)NR′—, where R′ is (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₅-C₂₀) aryl, (C₆-C₂₆) alkaryl, 5-20 memberedheteroaryl, or 6-26 membered alkheteroaryl. In another embodiment, R′ issubstituted with —OR, —SR, —NRR, —NO₂, —CN, halogen, —SO₂R, —C(O)R,—C(O)OR and —C(O)NRR, where each R is independently hydrogen, alkyl, oraryl.

In another embodiment, a non-amide linkage replaces one or more of theApoA-I Mimics' amide linkages and includes, but is not limited to,—CH₂NH—, —CH₂S—, —CH₂CH₂—, —CH═CH— (cis and trans), —C(O)CH₂—,—CH(OH)CH₂— and —CH₂SO—. Compounds having such non-amide linkages andmethods for preparing such compounds are well-known in the art (see,e.g., Spatola, March 1983, Vega Data Vol. 1, Issue 3; Spatola, 1983,“Peptide Backbone Modifications” In: Chemistry and Biochemistry of AminoAcids Peptides and Proteins, Weinstein, ed., Marcel Dekker, New York, p.267 (general review); Morley, 1980, Trends Pharm. Sci. 1:463-468; Hudsonet al., 1979, Int. J. Prot. Res. 14:177-185 (—CH₂NH—, —CH₂CH₂—); Spatolaet al., 1986, Life Sci. 38:1243-1249 (—CH₂—S); Hann, 1982, J. Chem. Soc.Perkin Trans. I. 1:307-314 (—CH═CH—, cis and trans); Almquist et al.,1980, J. Med. Chem. 23:1392-1398 (—COCH₂—); Jennings-White et al.,Tetrahedron. Lett. 23:2533 (—COCH₂—); European Patent Application EP45665 (1982) CA 97:39405 (—CH(OH)CH₂—); Holladay et al., 1983,Tetrahedron Lett. 24:4401-4404 (—C(OH)CH₂—); and Hruby, 1982, Life Sci.31:189-199 (—CH₂—S—).

Additionally, one or more of the ApoA-I Mimics' amide linkages can bereplaced with one or more peptidomimetic or amide mimetic moieties thatdo not significantly interfere with the structure or activity of thepeptides. Suitable amide mimetic moieties are described, for example, inOlson et al., 1993, J. Med. Chem. 36:3039-3049.

In some embodiments, the ApoA-I Mimic is in the form of apharmaceutically acceptable salt. The salt can be formed at theC-terminus or N-terminus or at an acidic or basic amino acid residueside chain.

In some embodiments, the pharmaceutically acceptable salt is a metalsalt, organic amine salt, or acid addition salt.

Metal salts can arise from the addition of an inorganic base to thepeptide of Formula I, II, or III. The inorganic base consists of a metalcation paired with a basic couterion such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal may be an alkali metal,alkaline earth metal, transition metal, or main group metal. In someembodiments, the metal is lithium, sodium, potassium, cerium, magnesium,manganese, iron, calcium, aluminum, or zinc.

Organic amine salts can arise from the addition of an organic amine tothe peptide of Formula I, II, or III. In some embodiments, the organicamine is triethylamine, ethanolamine, diethanolamine, triethanolamine,morpholine, piperidine, N-methylpiperidine, N-ethylpiperidine,dibenzylamine, piperazine, pyridine, pyrazine, or pipyrazine.

Acid addition salts arise from the addition of an acid to the peptide ofFormula I, II, or III. In some embodiments, the acid is organic. In someembodiments, the acid is inorganic. In other embodiments, the acid ishydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid,lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinicacid, gluconic acid, glucaronic acid, saccaric acid, formic acid,benzoic acid, glutamic acid, pantothenic acid, acetic acid, fumaricacid, succinic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, citric acid, or maleicacid. In still other embodiments, the acid addition salt is ahydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfite,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, tartrate, bitartrate, ascorbate, gentisinate, gluconate,glucaronate, saccarate, formate, benzoate, glutamate, pantothenate,acetate, fumarate, succinate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluoylsulfonate, citrate, or maleate salt.

In some embodiments, R¹ is an amino protecting group. In someembodiments, the amino protecting group is: (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₅-C₂₆) aryl, (C₆-C₂₆ aralkyl), 5- to20-membered heteroaryl, or 6- to 26-membered alkheteroaryl; —C(O)R;—C(O)OR; —SO₂R; or —SR, wherein R is H or (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₅-C₂₆) aryl, (C₆-C₂₆ aralkyl), 5- to20-membered heteroaryl, or 6- to 26-membered alkheteroaryl. In otherembodiments, the (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₅-C₂₆) aryl, (C₆-C₂₆ aralkyl), 5- to 20-membered heteroaryl, or 6- to26-membered alkheteroaryl is substituted with one or more of —OR^(a),—SR^(a), —NR^(a)R^(a), —NO₂, —CN, halogen, —SO₂R^(a), —C(O)R^(a),—C(O)OR^(a) and —C(O)NR^(a)R^(a), where each R^(a) is independentlyhydrogen, alkyl, or aryl. When R¹ is H, the number of amino protectinggroups in the ApoA-I Mimic is zero; and when R¹ is an amino protectinggroup, the number of amino protecting groups in the ApoA-I Mimic is 1.

In other embodiments, the amino protecting group is: dansyl;methoxycarbonyl; ethoxycarbonyl; 9-fluorenylmethoxycarbonyl;2-chloroethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl;2-phenylethoxycarbonyl; t-butoxycarbonyl; benzyloxycarbonyl;p-methoxybenzyloxycarbonyl; p-nitrobenzyloxycarbonyl;o-nitrobenzyloxycarbonyl; p-bromobenzyloxycarbonyl;p-chlorobenzyloxycarbonyl; p-iodobenzyloxycarbonyl;2,4-dichlorobenzyloxycarbonyl; diphenylmethoxycarbonyl;3,5-dimethoxybenzyloxycarbonyl; phenoxycarbonyl;2,4,6-tri-t-butylpenoxycarbonyl; 2,4,6-trimethylbenzyloxycarbonyl;formyl; acetyl; chloroacetyl; trichloroacetyl; trifluoroacetyl;phenylacetyl; picolinoyl; benzoyl; p-phenylbenzoyl; phthaloyl; methyl;t-butyl; allyl; [2-(trimethylsilyl)ethoxy]methyl; 2,4-dimethoxybenzyl;2,4-dinitrophenyl; benzyl; 4-methoxybenzyl; diphenylmethyl;triphenylmethyl; benzenesulfenyl; o-nitrobenzenesulfenyl;2,4-dinitrobenzenesulfenyl; p-toluenesulfonyl; benzenesulfonyl;2,3,6-trimethyl-4-methoxybenzenesulfonyl;2,4,6-trimethoxybenzenesulfonyl; 2,6-dimethyl-4-methoxybenzenesulfonyl;pentamethylbenzenesulfonyl; 4-methoxybenzenesulfonyl;2,4,6-trimethylbenzenesulfonyl; or benzylsulfonyl. In other embodiments,the amino protecting group is acetyl, formyl, or dansyl.

In some embodiments, R² is a carboxyl protecting group. In someembodiments, the carboxyl protecting group is: O—(C₁-C₆) alkyl,O—(C₂-C₆) alkenyl, O—(C₂-C₆) alkynyl, O—(C₅-C₂₆) aryl, O—(C₆-C₂₆aralkyl), O-(5- to 20-membered heteroaryl), or O-(6- to 26-memberedalkheteroaryl); or —NRR, wherein R is H or (C₁-C₆) alkyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₅-C₂₆) aryl, (C₆-C₂₆ aralkyl), 5- to20-membered heteroaryl, or 6- to 26-membered alkheteroaryl. In otherembodiments, the (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl,(C₅-C₂₆) aryl, (C₆-C₂₆ aralkyl), 5- to 20-membered heteroaryl, or 6- to26-membered alkheteroaryl is substituted with one or more of —OR^(a),—SR^(a), —NR^(a)R^(a), —NO₂, —CN, halogen, —SO₂R^(a), —C(O)R^(a),—C(O)OR^(a) and —C(O)NR^(a)R^(a), where each R^(a) is independentlyhydrogen, alkyl, or aryl. When R¹ is H, the number of carboxylprotecting groups in the ApoA-I Mimic is zero; and when R¹ is a carboxylprotecting group, the number of carboxyl protecting groups in the ApoA-IMimic is 1.

In other embodiments, the carboxyl protecting group is methoxy; ethoxy;9-fluorenylmethoxy; methoxymethoxy; methylthiomethoxy;tetrahydropyranoxy; tetrahydrofuranoxy; methoxyethoxymethoxy;benzyloxymethoxy; phenacyloxy; p-bromophenacyloxy; α-methylphenacyloxy;p-methoxyphenacyloxy; desyloxy; 2-chloroethoxy; 2,2,2-thrichloroethoxy,2-methylthioethoxy; 2-(p-toluenesulfonyl)methoxy; t-butoxy;cyclopentoxy; cyclohexoxy; allyloxy; methallyloxy; cinnamoxy;α-methylcinnamoxy; phenoxy; 2,6-dimethylphenoxy; 2,6-diisopropylphenoxy;benzyloxy; triphenylmethoxy; diphenylmethoxy; 2,4,6-trimethylbenzyloxy;p-bromobenzyloxy; o-nitrobenzyloxy; N,N-dimethylamido; pyrrolidinyl; orpiperidinyl.

Also included within the scope of the invention are protected forms ofthe ApoA-I Mimic, i.e., forms of the ApoA-I Mimic in which one or moreof its —NH₂ or —COOH groups are protected with a protecting group. Inone embodiment, one or more —NH₂ groups are protected with an aminoprotecting group as described above. In another embodiment, one or more—COOH groups are protected with a carboxyl protecting group as describedabove.

In one embodiment, the ApoA-I Mimics have the ability to form anamphipathic α-helix in the presence of one or more lipids. By“amphipathic” is meant that the α-helix has opposing hydrophilic andhydrophobic faces oriented along its long axis, i.e., one face of thehelix projects mainly hydrophilic side chains while the opposite faceprojects mainly hydrophobic side chains. FIGS. 1A and 1B present twoillustrative views of the opposing hydrophilic and hydrophobic faces ofan exemplary idealized amphipathic α-helix. FIG. 1A is aSchiffer-Edmundson helical wheel diagram (Schiffer and Edmundson, 1967,Biophys. J. 7:121-135). In the wheel, the long axis of the helix isperpendicular to the page. Starting with the N-terminus, successiveamino acid residues (represented by circles) are radially distributedabout the perimeter of a circle at 100° intervals. Thus, amino acidresidue n+1 is positioned 100° from residue n, residue n+2 is positioned100° from residue n+1, and so forth. The 100° placement accounts for the3.6 amino acid residues per turn that are typically observed in anidealized α-helix. In FIG. 1A, the opposing hydrophilic and hydrophobicfaces of the helix are clearly visible; hydrophilic amino acid residuesare represented as open circles and hydrophobic amino acid residues arerepresented as shaded circles.

FIG. 1B presents a helical net diagram of the idealized amphipathichelix of FIG. 1A. (Lim, 1978, FEBS Lett. 89:10-14). In a typical helicalnet diagram, the α-helix is presented as a cylinder that has been cutalong the center of its hydrophilic face and flattened. Thus, the centerof the hydrophobic face, determined by the hydrophobic moment of thehelix (Eisenberg et al., 1982, Nature 299:371-374), lies in the centerof the figure and is oriented so as to rise out of the plane of thepage. An illustration of the helical cylinder prior to being cut andflattened is depicted in FIG. 1C. By cutting the cylinder alongdifferent planes, different views of the same amphipathic helix can beobserved, and different information about the properties of the helixobtained.

While not being bound by any particular theory, it is believed thatcertain structural and/or physical properties of the amphipathic helixformed by the ApoA-I Mimics, can be important for activity. Theseproperties include the degree of amphipathicity, overall hydrophobicity,mean hydrophobicity, hydrophobic and hydrophilic angles, hydrophobicmoment, mean hydrophobic moment, and net charge of the α-helix.

The degree of amphipathicity (degree of asymmetry of hydrophobicity) ofthe amphiphathic helix formed by the ApoA-I Mimics can be convenientlyquantified by calculating the hydrophobic moment (μ_(H)) of the helix.Methods for calculating μ_(H) for a particular peptide sequence arewell-known in the art, and are described, for example in Eisenberg,1984, Ann. Rev. Biochem. 53:595-623. The actual μ_(H) obtained for aparticular peptide will depend on the total number of amino acidresidues composing the peptide. Thus, it is generally not informative todirectly compare ρl_(H) for peptides of different lengths.

The amphipathicities of peptides of different lengths can be directlycompared by way of the mean hydrophobic moment (<μ_(H)>). The meanhydrophobic moment can be obtained by dividing μ_(H) by the number ofresidues in the helix (i.e., <μ_(H)>=μ_(H)/N). Generally, ApoA-I Mimicswhich exhibit a <μ_(H)> in the range of 0.45 to 0.65, as determinedusing the normalized consensus hydrophobicity scale of Eisenberg(Eisenberg, 1984, J. Mol. Biol. 179:125-142) are considered to be withinthe scope of the present invention. In one embodiment, <μ_(H)> is in therange of 0.50 to 0.60.

The overall or total hydrophobicity (H_(o)) of a peptide can beconveniently calculated by taking the algebraic sum of thehydrophobicities of each amino acid residue in the peptide (i.e.,

$ {H_{o} = {\sum\limits_{i = 1}^{N}H_{i}}} ),$where N is the number of amino acid residues in the peptide and H, isthe hydrophobicity of the ith amino acid residue). The meanhydrophobicity (<H_(o)>) is the hydrophobicity divided by the number ofamino acid residues (i.e., <H_(o)>=H_(o)/N). Generally, ApoA-I Mimicsthat exhibit a mean hydrophobicity in the range of −0.050 to −0.070, asdetermined using the normalized consensus hydrophobicity scale ofEisenberg (Eisenberg, 1984, J. Mol. Biol. 179:125-142) are considered tobe within the scope of the present invention. In one embodiment, themean hydrophobicity is in the range of −0.030 to −0.055.

The total hydrophobicity of the hydrophobic face)(H_(o) ^(pho)) of anamphipathic helix can be obtained by taking the sum of thehydrophobicities of the hydrophobic amino acid residues which fall intothe hydrophobic angle as defined below (i.e.,

$H_{o}^{pho} = {\sum\limits_{i = 1}^{N}H_{i}}$where H_(i), is as previously defined and N_(H) is the total number ofhydrophobic amino acid residues in the hydrophobic face). The meanhydrophobicity of the hydrophobic face (<H_(o) ^(pho)>) is H_(o)^(pho)/N_(H) where N_(H) is as defined above. Generally, ApoA-I Mimicswhich exhibit a <H_(o) ^(pho)> in the range of 0.90 to 1.20, asdetermined using the consensus hydrophobicity scale of Eisenberg(Eisenberg, 1984, supra; Eisenberg et al., 1982, supra) are consideredto be within the scope of the present invention. In one embodiment, the<H_(o) ^(pho)> is in the range of 0.94 to 1.10.

The hydrophobic angle (pho angle) is generally defined as the angle orarc covered by the longest continuous stretch of hydrophobic amino acidresidues when the peptide is arranged in the Schiffer-Edmundson helicalwheel representation (i.e., the number of contiguous hydrophobicresidues on the wheel multiplied by 20°). The hydrophilic angle (phiangle) is the difference between 360° and the pho angle (i.e., 360°-phoangle). Those of skill in the art will recognize that the pho and phiangles can depend, in part, on the number of amino acid residues in thepeptide. For example, referring to FIG. 2, it can be seen that only 18amino acid residues fit around one rotation of the Schiffer-Edmundsonhelical wheel for Segrest's consensus 22-mer peptidePro-Val-Leu-Asp-Glu-Phe-Arg-Glu-Lys-Leu-Asn-Glu-Glu-Leu-Glu-Ala-Leu-Lys-Gln-Lys-Leu-Lys(SEQ ID NO. 1). Fewer amino acid residues leave a gap in the wheel; moreamino acid residues cause certain positions of the wheel to be occupiedby more than one amino acid residue.

In the case of peptides having 15 or more amino acid residues, such asan ApoA-I Mimic having from 15 to 29 residues, a “continuous” stretch ofhydrophobic amino acid residues is meant that at least one amino acidresidue at positions along the wheel containing two or more amino acidresidues is a hydrophobic amino acid residue. Thus, referring to FIG. 2,the pho angle is the arc covered by residues 16, 2, 6, 17, 10, 3, and 14despite the occurrence of a hydrophilic residue at position 20, as theresidue at position 2, which shares the same position on the wheel, is ahydrophobic residue. Typically, ApoA-I Mimics having a pho angle in therange of 160° to 220° are considered to be within the scope of theinvention. In some embodiments, the pho angle is in the range of 180° to200°.

In Peptide 16 (Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-AsnLeu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 16)) or apharmaceutically acceptable salt thereof, an illustrative ApoA-I Mimic,positively-charged amino acid residues are clustered at the lastN-terminal turn of the helix. While not being bound by any particulartheory, it is believed that the cluster of basic residues at theN-terminus stabilizes the helix through charge (NH₃ ⁺)-helix dipoleelectrostatic interactions. It is also thought that stabilization occursthrough hydrophobic interactions between lysine side chains and thehelix core (see, Groebke et al., 1996, Proc. Natl. Acad. Sci. U.S.A.93:4025-4029; Esposito et al., 1997, Biopolymers 41:27-35).

With the exception of the positively-charged N-terminal cluster,negative charges in Peptide 16 (SEQ ID NO: 16) or a pharmaceuticallyacceptable salt thereof are distributed on the rest of the hydrophilicface, with at least one negatively charged (acidic) amino acid residueper turn, resulting in a continuous stretch of negative charges alongthe hydrophilic face of the helix. One positive charge is located atresidue 16, which potentially contributes to helix stability by forminga salt bridge with an acidic residue one turn away on the helix.

It is believed that NMR studies of Peptide 16 (SEQ ID NO: 16) or apharmaceutically acceptable salt thereof would indicate that amino acidresidues 13, 14, 17, and 20 of the peptide form a hydrophobic clusternear the C-terminus of the helix. Phe-17 is centered in this cluster andis believed to play an important role in stabilizing the hydrophobiccluster.

While not being bound by any particular theory, it is believed that thehydrophobic cluster formed by residues 13, 14, 17, and 20 of Peptide 16(SEQ ID NO: 16) or a pharmaceutically acceptable salt thereof issignificant in effecting lipid binding and LCAT activation. Amphipathicpeptides are expected to bind phospholipids by pointing theirhydrophobic faces towards the alkyl chains of the lipid moieties. Thus,it is believed that this highly hydrophobic cluster contributes to thestrong lipid affinities observed for the ApoA-I Mimics of the invention.Since lipid binding is a prerequisite for LCAT activation, it isbelieved that this hydrophobic cluster is also essential for LCATactivation.

Aromatic residues can be important in anchoring peptides and proteins tolipids (De Kruijff, 1990, Biosci. Rep. 10:127-130; O'Neil and De Grado,1990, Science 250:645-651; Blondelle et al., 1993, Biochim. Biophys.Acta 1202:331-336). Thus, it is further believed that Phe-17, which ispositioned at the center of the hydrophobic cluster, may also play a keyrole in anchoring Peptide 16 (SEQ ID NO: 16) or a pharmaceuticallyacceptable salt thereof to a lipid.

The long axis of the α-helix formed by the ApoA-I Mimics typically hasan overall curved shape. In typical amphipathic helices, it has beenfound that the lengths of the hydrogen bonds of the hydrophilic andhydrophobic faces vary such that the hydrophobic side of the helix isconcave (Barlow and Thornton, 1988, J. Mol. Biol. 201:601-619; Zhou etal., 1992, J. Am. Chem. Soc. 33:11174-11183; Gesell et al., 1997, J.Biomol. NMR 9:127-135). While not being bound by theory, it is believedthat the overall curvature of the hydrophobic face of the helix might beimportant in binding discoidal complexes—a curved helix permits thepeptide to “fit” better around the edges of discoidal particles, therebyincreasing the stability of the peptide-disc complex.

In the generally accepted structural model of ApoA-I, the amphipathicα-helices are packed around the edge of the discoidal HDL (see, FIG.4B). In this model, the helices are assumed to be aligned with theirhydrophobic faces pointing towards the lipid acyl chains (Brasseur etal., 1990, Biochim. Biophys. Acta 1043:245-252). The helices arearranged in an antiparallel fashion, and a cooperative effect betweenthe helices is thought to contribute to the stability of the discoidalHDL complex (Brasseur et al., supra). It has been proposed that onefactor that contributes to the stability of the HDL discoidal complex isthe existence of ionic interactions between acidic and basic residuesresulting in the formation of intermolecular salt bridges or hydrogenbonds between residues on adjacent anti-parallel helices. In this model,the peptides are considered not as a single entity, but as ininteraction with at least two other neighboring peptide molecules (FIG.4B).

It is also generally accepted that intramolecular hydrogen bond or saltbridge formation between acidic and basic residues, respectively, atpositions i and i+3 of the helix stabilize the helical structure(Marqusee et al:, 1985, Proc. Natl. Acad. Sci. USA 84(24):8898-8902).

Thus, the ApoA-I Mimics have the ability to form intermolecularhydrogen-bonds with one another when aligned in an antiparallel fashionwith their hydrophobic faces pointing in the same direction, such aswould be the case when the peptides are bound to lipids. The ApoA-IMimics also have the ability to form intramolecular hydrogen bonds orsalt bridges near the N- and C-termini of the helix.

Furthermore, when arranged in this anti-parallel fashion, the helicesare closely packed; there is no steric hindrance preventing closecontact between the helices. The ApoA-I Mimics have the ability toclosely pack and ionically interact to form intra- and/orinter-molecular salt bridges and/or hydrogen bonds when bound to lipidsin an antiparallel fashion.

The ApoA-I Mimics can self-associate. The self-association phenomenondepends on the conditions of pH, peptide concentration and ionicstrength, and can result in several states of association, frommonomeric to several multimeric forms (FIG. 4A). The hydrophobic core ofpeptide aggregates favors hydrophobic interactions with lipids. Theability of the peptides to aggregate even at very low concentrations mayfavor their binding to lipids. It is thought that in the core of thepeptide aggregates peptide-peptide interactions also occur and maycompete with lipid-peptide interactions.

The hydrophobic core of the aggregates of the ApoA-I Mimics favorshydrophobic interactions with lipids. The ability of the ApoA-I Mimicsto aggregate even at very low concentrations can favor their binding tolipids. Interactions between the ApoA-I Mimics and lipids lead to theformation of peptide-lipid complexes. As illustrated in FIG. 4A, thetype of complex obtained (comicelles, discs, vesicles or multilayers)can depend on the lipid:peptide molar ratio, with comicelles generallybeing formed at low lipid:peptide molar ratios and discoidal andvesicular or multilayer complexes being formed with increasinglipid:peptide molar ratios. Micelles are typically formed at ratios ofabout 2 moles of lipid: about 1 mole of ApoA-I or about 2 moles oflipid: about 6 to about 10 moles of ApoA-I Mimic. Discoidal complexesare typically formed at ratios of about 50-100 moles of lipid: about 1mole of ApoA-I or about 6 to about 10 moles of ApoA-I Mimic. Vesicularcomplexes are typically formed at ratios of about 200 to about 300 molesof lipid: about 1 mole of ApoA-I or about 6 to about 10 moles of ApoA-IMimic. This characteristic has been described for amphipathic peptides(Epand, The Amphipathic Helix, 1993) and for ApoA-I (Jones, 1992,Structure and Function of Apolipoproteins, Chapter 8, pp. 217-250). Thelipid:peptide molar ratio also determines the size and composition ofthe complexes.

D. Altered Forms of the Peptides of Formula I, II, and III andPharmaceutically Acceptable Salts Thereof

In other embodiments, the ApoA-I Mimics have 22 amino acid residues orfewer. Indeed, truncated or internally deleted forms of Formula I, II,or III containing 21, 20, 19, 18, 17, 16, or even 15 amino acid residuesthat substantially retain the overall characteristics and properties ofthe amphipathic helix formed by the ApoA-I Mimics are considered to bewithin the scope of the present invention.

In one embodiment of the invention, truncated forms of the ApoA-I Mimicsare obtained by deleting one or more amino acid residues from the N-and/or C-terminus. Internally deleted forms of the ApoA-I Mimics areobtained by deleting one or more amino acid residues from internalpositions within the ApoA-I Mimics. The internal amino acid residuesdeleted can be consecutive residues or non-consecutive residues.

Those of skill in the art will recognize that deleting an internal aminoacid residue from an ApoA-I Mimic can cause the plane of thehydrophilic-hydrophobic interface of the helix to rotate by 100° at thepoint of the deletion. As such rotations can significantly alter theamphipathic properties of the resultant helix, in one embodiment of theinvention one or more amino acid residues are deleted so as tosubstantially retain the alignment of the plane of thehydrophilic-hydrophobic interface along the entire long axis of thehelix.

This can be conveniently achieved by deleting a sufficient number ofconsecutive or non-consecutive amino acid residues such that onecomplete helical turn is deleted. An idealized α-helix has 3.6 residuesper turn. Thus, in one embodiment, groups of 3-4 consecutive ornon-consecutive amino acid residues are deleted. Whether 3 amino acidresidues or 4 amino acid residues are deleted can depend upon theposition within the helix of the first residue to be deleted.Determining the appropriate number of consecutive or non-consecutiveamino acid residues that constitute one complete helical turn from anyparticular starting point within an amphipathic helix is well within thecapabilities of those of skill in the art.

The ApoA-I Mimics can also be extended at one or both termini orinternally with additional amino acid residues that do not substantiallyinterfere with, and in some embodiments even enhance, the structuraland/or functional properties of the peptides. Indeed, extended ApoA-IMimics containing as many as 23, 24, 25, 26, 27, 28, or 29 amino acidresidues are also within the scope of the invention. Such extendedApoA-I Mimics may substantially retain the net amphipathicity and otherproperties of the ApoA-I Mimics. Of course, it will be recognized thatadding amino acid residues internally can rotate the plane of thehydrophobic-hydrophilic interface at the point of the insertion in amanner similar to that described above for internal deletions. Thus, theconsiderations discussed above in connection with internal deletionsapply to internal additions, as well.

In one embodiment, the ApoA-I Mimics are extended at their N- and/orC-terminus by an amino acid sequence having from 1 to 7 residues.

In one embodiment, the ApoA-I Mimics are extended at their N- and/orC-terminus by least one helical turn. Such extensions stabilize thehelical secondary structure in the presence of lipids, such as theend-cap amino acid residues and segments previously described.

In another embodiment, the ApoA-I Mimics are extended at the N-terminusby a single basic amino acid residue, such as Lys (K). In oneembodiment, X¹ is Lys, X² is Lys, X³ is Leu, X⁴ is Lys, X⁵ is Gln, X⁶ isLys, X⁷ is Leu, X⁸ is Ala, X⁹ is Glu, X¹⁰ is Leu, X¹¹ is Leu, X¹² isGlu, X¹³ is Asn, X¹⁴ is Leu, X¹⁵ is Leu, X¹⁶ is Glu, X¹⁷ is Arg, X¹⁸ isPhe, X¹⁹ is Leu, X²⁰ is Asp, X²¹ is Leu, X²² is Val, and X²³ is Inp.

Also included within the scope of the present invention are “protected”forms of the ApoA-I Mimics, i.e., forms of the ApoA-I Mimics in whichthe R¹ is an amino protecting group and/or R² is a carboxy protectinggroup. It is believed that removing the N- and/or C-terminal charges ofthe ApoA-I Mimics having 18 or fewer amino acid residues (bysynthesizing N-acylated peptide amides/ester/hydrazides/alcohols andsubstitutions thereof) can result in mimics which approach, and in someembodiments even exceed, the activity of the unprotected form of themimic. In some embodiments having 22 or more amino acid residues, it isbelieved that blocking the N- or C-terminus can result in ApoA-I Mimicsthat exhibit lower activity than the unblocked forms. However,protecting both the N- and C-termini of ApoA-I Mimics of 22 or moreamino acid residues can restore activity. Thus, in one embodiment of theinvention, either the N- and/or C-terminus (in another embodiment, bothtermini) of ApoA-I Mimics having 18 or fewer amino acid residues areprotected, whereas the N- and C-termini of peptides having 22 or moreamino acid residues are either both protected or both unprotected.Typical N-terminal blocking groups include RC(O)—, where R is —H,(C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, (C5-C20) aryl, (C₆-C₂₆)alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl.Particular N-terminal blocking groups include acetyl, formyl and dansyl.Typical C-terminal blocking groups include —C(O)NRR and —C(O)OR, whereeach R is independently defined as above. Particular C-terminal blockinggroups include those where each R is independently methyl. While notbeing bound by any particular theory, it is believed that such terminalblocking groups stabilize the α-helix in the presence of lipids (see,e.g., Venkatachelapathi et al., 1993, PROTEINS: Structure, Function andGenetics 15:349-359).

E. Dimers, Trimers, Tetramers, and Multimers of the Peptides of FormulaI, II, or III and Pharmaceutically Acceptable Salts Thereof

The structure of native ApoA-I contains eight helical units that arethought to act in concert to bind lipids (Nakagawa et al., 1985, J. Am.Chem. Soc. 107:7087-7092; Anantharamaiah et al., 1985, J. Biol. Chem.260:10248-10262; Vanloo et al., 1991, J. Lipid Res. 32:1253-1264; Mendezet al., 1994, J. Clin. Invest. 94:1698-1705; Palgunari et al., 1996,Arterioscler. Thromb. Vasc. Biol. 16:328-338; Demoor et al., 1996, Eur.J. Biochem. 239:74-84). Thus, also included in the present invention aredimers, trimers, tetramers and even higher order polymers (“multimers”)of the ApoA-I Mimics. Such multimers may be in the form of tandemrepeats, branched networks or combinations thereof. The ApoA-I Mimicsmay be directly attached to one another or separated by one or morelinkers.

The ApoA-I Mimics that comprise the multimers may be the peptides ofFormula I, II, or III, analogs of Formula I, II, or III, altered formsof Formula I, II, or III, truncated or internally deleted forms ofFormula I, II, or III, extended forms of Formula I, II, or III, and/orcombinations thereof. The ApoA-I Mimics can be connected in ahead-to-tail fashion (i.e., N-terminus to C-terminus), a head-to-headfashion, (i.e., N-terminus to N-terminus), a tail-to-tail fashion (i.e.,C-terminus to C-terminus), or combinations thereof and pharmaceuticallyacceptable salts thereof.

In one embodiment of the invention, the multimers are tandem repeats oftwo, three, four and up to about ten ApoA-I Mimics. In one embodiment,the multimers are tandem repeats of from 2 to 8 peptides. Thus, in oneembodiment, the invention provides multimers having the followingstructural formula:HH

LL_(m)-HH

_(n)LL_(m)-HH  (IV)wherein:

each m is independently an integer from 0 to 1, and in one embodiment mis 1;

n is an integer from 0 to 10, and in one embodiment n is an integer from0 to 8;

each “HH” is independently a radical derived from an ApoA-I Mimic; and

each “LL” independently represents a linker.

In structure (IV), the linker LL can be any bifunctional moleculecapable of covalently linking two peptides to one another. Thus,suitable linkers are bifunctional molecules in which the functionalgroups are capable of being covalently attached to the N- and/orC-terminus of a peptide. Functional groups suitable for attachment tothe N- or C-terminus of peptides are well known in the art, as aresuitable chemistries for effecting such covalent bond formation.

The linker can be flexible, rigid or semi-rigid, depending on thedesired properties of the multimer. Suitable linkers include, forexample, amino acid residues such as Pro, azPro, Pip, azPip, or Gly orpeptide segments containing from about 2 to about 5, 10, 15 or 20 oreven more amino acid residues, bifunctional organic compounds such asH₂N(CH₂)_(n)COOH, HO(CH₂)nCOOH, and HO(CH₂CH₂O)nCH₂CH₂COOH, where n isan integer from 1 to 12, and the like. Examples of such linkers, as wellas methods of making such linkers and compounds incorporating suchlinkers are well-known in the art (see, e.g., Hunig et al., 1974, Chem.Ber. 100:3039-3044; Basak et al., 1994, Bioconjug. Chem. 5(4):301-305).

In one embodiment of the invention, the tandem repeats are internallypunctuated by a single proline residue. In those instances where theApoA-I Mimics do not contain an N- or C-terminal proline residue, LL canbe Pro, D-Pro, azPro, Pip, D-Pip, or azPip and m is 1.

In some embodiments of the invention, it can be desirable to employcleavable linkers that permit the release of one or more helicalsegments (HH) under certain conditions. Suitable cleavable linkersinclude peptides having sequences of amino acid residues that arerecognized by proteases, oligonucleotides that can be cleaved byendonucleases and organic compounds that can be cleaved via chemicalmeans, such as under acidic, basic or other conditions. Typically, thecleavage conditions will be relatively mild so as not to denature orotherwise degrade the helical segments and/or non-cleaved linkerscomposing the multimers.

Peptide and oligonucleotide linkers that can be selectively cleaved, aswell as means for cleaving the linkers are well known and will bereadily apparent to those of skill in the art. Suitable organic compoundlinkers that can be selectively cleaved will be apparent to those ofskill in the art, and include those described, for example, in WO94/08051, as well as the references cited therein.

In one embodiment, the linkers employed are peptides that are substratesfor endogenous circulatory enzymes, thereby permitting the multimers tobe selectively cleaved in vivo. An endogenous enzyme suitable forcleaving the linkers is, for example, proapolipoprotein A-Ipropeptidase. Appropriate enzymes, as well as peptide segments that actas substrates for such enzymes, are well-known in the art (see, e.g.,Edelstein et al., 1983, J. Biol. Chem. 258:11430-11433; Zanis, 1983,Proc. Natl. Acad. Sci. USA 80:2574-2578).

In one embodiment, linkers of sufficient length and flexibility are usedso as to permit the helical segments (HH) of structure (II) to align inan antiparallel fashion and form intermolecular hydrogen-bonds or saltbridges in the presence of lipids. Linkers of sufficient length andflexibility include, but are not limited to, a residue or radical ofPro, D-Pro, azPro, Pip, D-Pip, azPip, Gly, Cys-Cys, H₂N(CH₂)_(n)COOH,HO(CH₂)nCOOH, or HO(CH₂CH₂O)nCH₂CH₂COOH where n is 1 to 12, or 4 to 6;H₂N-aryl-COOH and carbohydrates.

Alternatively, as the native apolipoproteins permit cooperative bindingbetween antiparallel helical segments, peptide linkers which correspondin primary sequence to the peptide segments connecting adjacent helicesof the native apolipoproteins, including, for example, ApoA-I, ApoA-II,ApoA-IV, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE and ApoJ can beconveniently used to link the ApoA-I Mimics of Formula I. Thesesequences are well known in the art (see, e.g., Rosseneu et al.,“Analysis of the Primary and of the Secondary Structure of theApolipoproteins,” In: Structure and Function of Lipoproteins, Ch. 6,159-183, CRC Press, Inc., 1992).

Other linkers which permit the formation of intermolecular hydrogenbonds or salt bridges between tandem repeats of antiparallel helicalsegments include peptide reverse turns such as β-turns and γ-turns, aswell as organic molecules that mimic the structures of peptide β-turnsand/or γ-turns. Generally, reverse turns are segments of peptide thatreverse the direction of the polypeptide chain so as to allow a singlepolypeptide chain to adopt regions of antiparallel β-sheet orantiparallel α-helical structure. β-Turns generally are composed of fouramino acid residues and γ-turns are generally composed of three aminoacid residues.

The conformations and sequences of many peptide β-turns have beenwell-described in the art and include, by way of example and notlimitation, type-I, type-I′, type-II, type-II′, type-III, type-III',type-IV, type-V, type-V′, type-VIa, type-VIb, type-VII and type-VIII(see, Richardson, 1981, Adv. Protein Chem. 34:167-339; Rose et al.,1985, Adv. Protein Chem. 37:1-109; Wilmot et al., 1988, J. Mol. Biol.203:221-232; Sibanda et al., 1989, J. Mol. Biol. 206:759-777; Tramontanoet al., 1989, Proteins: Struct. Funct. Genet. 6:382-394).

The specific conformations of short peptide turns such as β-turns dependprimarily on the positions of certain amino acid residues in the turn(usually Gly, Asn or Pro). Generally, the type-I β-turn is compatiblewith any amino acid residue at positions 1 through 4 of the turn, exceptthat Pro cannot occur at position 3. Gly predominates at position 4 andPro predominates at position 2 of both type-I and type-II turns. Asp,Asn, Ser and Cys residues frequently occur at position 1, where theirside chains often hydrogen-bond to the NH of residue 3.

In type-II turns, Gly and Asn occur most frequently at position 3, asthey adopt the required backbone angles most easily. Ideally, type-I′turns have Gly at positions 2 and 3, and type-II′ turns have Gly atposition 2. Type-III turns generally can have most amino acid residues,but type-III′ turns usually require Gly at positions 2 and 3. Type-VIaand VIb turns generally have a cis peptide bond and Pro as an internalresidue. For a review of the different types and sequences of β-turns inproteins and peptides the reader is referred to Wilmot et al., 1988, J.Mol. Biol. 203:221-232.

The conformation and sequences of many peptide γ-turns have also beenwell-described in the art (see, e.g., Rose et al., 1985, Adv. ProteinChem. 37:1-109; Wilmer-White et al., 1987, Trends Biochem. Sci.12:189-192; Wilmot et al., 1988, J. Mol. Biol. 203:221-232; Sibanda etal., 1989, J. Mol. Biol. 206:759-777; Tramontano et al., 1989, Proteins:Struct. Funct. Genet. 6:382-394). All of these types of β-turns andγ-turn structures and their corresponding sequences, as well as laterdiscovered peptide β-turns and γ-turn structures and sequences, arespecifically included in the invention.

Alternatively, the linker (LL) can comprise an organic molecule ormoiety that mimics the structure of a peptide β-turn or γ-turn. Suchβ-turn and/or γ-turn mimetic moieties, as well as methods forsynthesizing peptides containing such moieties, are well known in theart, and include, among others, those described in Giannis and Kolter,1993 Angew. Chem. Intl. Ed. Eng. 32:1244-1267; Kahn et al., 1988, J.Molecular Recognition 1:75-79; and Kahn et al., 1987, Tetrahedron Lett.28:1623-1626.

In still another embodiment of the invention, the multimers are in theform of branched networks (see, e.g., FIG. 3). Such networks areconveniently obtained through the use of multifunction linking moietiesthat permit more than two helical units to be attached to a simplelinking moiety. Thus, branched networks employ molecules having three,four or even more functional groups that are capable of covalentlyattaching to the N- and/or C-terminus of a peptide. Suitable linkingmoieties include, for example, residues of amino acids having sidechains bearing hydroxyl, sulfanyl, amino, carboxyl, amide and/or esterfunctionalities, such as, for example, Ser (S), Thr (T), Cys (C), Tyr(Y), Asn (N), Gln (Q), Lys (K), Arg (R), Orn, Asp (D) and Glu (E); aswell as the corresponding D-enantiomer of each of the foregoing; orresidues of other organic molecules containing such functional groups.

The helical segments attached to a single linking moiety need not beattached via like termini. Indeed, in some embodiments the helicalsegments are attached to a single linking moiety so as to be arranged inan antiparallel fashion, i.e., some of the helices are attached viatheir N-termini, others via their C-termini.

The helical segments can be attached directly to the linking moiety, orcan be spaced from the linking moiety by way of one or more bifunctionallinkers (LL), as previously described.

Referring to FIGS. 3A and 3B, it can be seen that a branched network canbe described in terms of the number of “nodes” comprising the network,where each multifunctional linking moiety constitutes a node. In FIGS.3A and 3B, helical segments (i.e., ApoA-I Mimics) are illustrated ascylinders, and multifunctional linking moieties (or nodes) as circles(●), where the number of lines emanating from the circle indicates the“order” (or number of functional groups) of the multifunctional linkingmoiety.

The number of nodes in the network will generally depend on the totaldesired number of helical segments, and will typically be from about 1to 2. Of course, it will be appreciated that for a given number ofdesired helical segments, networks having higher order linking moietieswill have fewer nodes. For example, referring to FIGS. 3A and 3B, atertiary-order network (i.e., a network having trifunctional linkingmoieties) of seven helical units has three nodes (FIG. 3A), whereas aquaternary order network (i.e., a network having tetrafunctional linkingmoieties) of seven helical units has only two nodes (FIG. 3B).

The networks can be of uniform order, i.e., networks in which all nodesare, for example, trifunctional or tetrafunctional linking moieties, orcan be of mixed order, e.g., networks in which the nodes are mixturesof, for example, trifunctional and tetrafunctional linking moieties. Ofcourse, it is to be understood that even in uniform order networks thelinking moieties need not be identical. A tertiary order network canemploy, for example, two, three, four or even more differenttrifunctional linking moieties.

Like the linear multimers, the helical segments comprising the branchednetwork can be, but need not be, identical.

An example of such a mixed order branched network is illustrated in FIG.3C. In FIG. 3C, helical segments (i.e., ApoA-I Mimics) are illustratedas cylinders and multifunctional linking moieties as circles (●), wherethe number of lines emanating from the circle indicates the “order” (ornumber of functional groups) of the multifunctional linking moiety.Lines connecting helical segments represent bifunctional linkers LL, aspreviously described. Helical segments which comprise the branchednetworks can be tandem repeats of ApoA-I Mimics, as previouslydescribed.

In one illustrative embodiment, the branched networks of the inventionare described by the formula:X—N_(ya)—X_((ya-1))

N_(yb)—X_((yb-1)))_(p)  (V)wherein:each X is independently a radical derived from a multimer of theformula:HH

LL_(m)-HH

_(n)LL_(m)-HH  (VI)wherein:

each HH is independently a radical derived from an ApoA-I Mimic;

each LL is independently a bifunctional linker;

each m is independently an integer from 0 to 1;

each n is independently an integer from 0 to 8;

N_(ya) and N_(yb) are each independently a multifunctional linkingmoiety where y_(a) and y_(b) represent the number of functional groupson N_(ya) and N_(yb), respectively;

each y_(a) or y_(b) is independently an integer from 3 to 8; and

p is an integer from 0 to 7.

In one embodiment, the branched network comprises a “Lys tree,” i.e., anetwork wherein the multifunctional linking moiety is one or more Lys(K) residues (see, e.g., FIG. 3D).

In one illustrative embodiment, the “Lys tree” branched networks of theinvention are described by the formulae:

wherein:

each X is independently a radical derived from a multimer of theformula:HH

LL_(m)-HH

_(n)LL_(m)-HH  (VI)

each HH is independently a radical derived from an ApoA-I Mimic ofFormula I;

each LL is independently a bifunctional linker;

each n is independently an integer from 0 to 8;

each m is independently an integer from 0 to 1;

R₁ is —OR or —NRR; and

each R is independently —H, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆)alkynyl; or (C₅-C₂₆) aryl.

Some additional illustrative ApoA-I Mimics are set forth in Table 7below:

TABLE 7 Peptide 41Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Inp (SEQ. ID. NO. 41) Peptide 42Lys-Leu-Lys-Gln-Lys-Trp-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 42) Peptide 43Lys-Leu-Lys-Lys-Lys-Leu-Ala-Lys-Leu-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 43) Peptide 44Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Glu-Asn-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 44) Peptide 45Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-(D-Val)-Inp (SEQ. ID. NO. 45) Peptide 46Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Inp (SEQ. ID. NO. 46) Peptide 47Lys-Lys-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 47) Peptide 48Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 48) Peptide 49Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Inp (SEQ. ID. NO. 49) Peptide 50Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asn-Leu-Leu-Glu-Asp-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Inp (SEQ. ID. NO. 50) Peptide 51Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 51) Peptide 52Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Inp(SEQ. ID. NO. 52) Peptide 53Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp (SEQ. ID. NO. 53) Peptide 54Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 54) Peptide 55Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp(SEQ. ID. NO. 55) Peptide 56Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 56) Peptide 57Lys-Leu-Lys-Gln-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 57) Peptide 58Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 58) Peptide 59Lys-Lys-Leu-Gln-Leu-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Inp(SEQ. ID. NO. 59) Peptide 60Lys-Lys-Leu-Gln-Ala-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Inp(SEQ. ID. NO. 60) Peptide 61Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 61) Peptide 62Lys-Leu-Lys-Lys-Gln-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Inp(SEQ. ID. NO. 62) Peptide 63Lys-Leu-Lys-Gln-Glu-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp(SEQ. ID. NO. 63) Peptide 133Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Nip (SEQ. ID. NO. 133) Peptide 134Lys-Leu-Lys-Gln-Lys-Trp-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 134) Peptide 135Lys-Leu-Lys-Lys-Lys-Leu-Ala-Lys-Leu-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 135) Peptide 136Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Glu-Asn-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 136) Peptide 137Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-(D-Val)-Nip (SEQ. ID. NO. 137) Peptide 138Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Nip (SEQ. ID. NO. 138) Peptide 139Lys-Lys-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 139) Peptide 140Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 140) Peptide 141Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Nip (SEQ. ID. NO. 141) Peptide 142Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asn-Leu-Leu-Glu-Asp-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 142) Peptide 143Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 143) Peptide 144Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Nip(SEQ. ID. NO. 144) Peptide 145Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 145) Peptide 146Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 146) Peptide 147Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip(SEQ. ID. NO. 147) Peptide 148Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 148) Peptide 149Lys-Leu-Lys-Gln-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 149) Peptide 150Lys-Leu-Lys-Lys-Gln-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 150) Peptide 151Lys-Lys-Leu-Gln-Leu-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Nip(SEQ. ID. NO. 151) Peptide 152Lys-Lys-Leu-Gln-Ala-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Nip(SEQ. ID. NO. 152) Peptide 153Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip(SEQ. ID. NO. 153) Peptide 154Lys-Leu-Lys-Lys-Gln-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Nip (SEQ. ID. NO. 154) Peptide 155Lys-Leu-Lys-Gln-Glu-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip (SEQ. ID. NO. 155) Peptide 253Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPro (SEQ. ID. NO. 253) Peptide 254Lys-Leu-Lys-Gln-Lys-Trp-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 254) Peptide 255Lys-Leu-Lys-Lys-Lys-Leu-Ala-Lys-Leu-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 255) Peptide 256Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Glu-Asn-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 256) Peptide 257Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-(D-Val)-azPro (SEQ. ID. NO. 257) Peptide 258Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-azPro (SEQ. ID. NO. 258) Peptide 259Lys-Lys-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 259) Peptide 260Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 260) Peptide 261Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-azPro (SEQ. ID. NO. 261) Peptide 262Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asn-Leu-Leu-Glu-Asp-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 262) Peptide 264Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-azPro(SEQ. ID. NO. 264) Peptide 269Lys-Leu-Lys-Gln-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 269) Peptide 271Lys-Lys-Leu-Gln-Leu-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-azPro (SEQ. ID. NO. 271) Peptide 272Lys-Lys-Leu-Gln-Ala-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-azPro (SEQ. ID. NO. 272) Peptide 273Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 273) Peptide 274Lys-Leu-Lys-Lys-Gln-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPro (SEQ. ID. NO. 274) Peptide 275Lys-Leu-Lys-Gln-Glu-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro (SEQ. ID. NO. 275) Peptide 345Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Pip (SEQ. ID. NO. 345) Peptide 346Lys-Leu-Lys-Gln-Lys-Trp-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 346) Peptide 347Lys-Leu-Lys-Lys-Lys-Leu-Ala-Lys-Leu-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 347) Peptide 348Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Glu-Asn-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 348) Peptide 349Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-(D-Val)-Pip (SEQ. ID. NO. 349) Peptide 350Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Pip (SEQ. ID. NO. 350) Peptide 351Lys-Lys-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 351) Peptide 352Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip (SEQ. ID. NO. 352) Peptide 353Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Pip (SEQ. ID. NO. 353) Peptide 354Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asn-Leu-Leu-Glu-Asp-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Pip (SEQ. ID. NO. 354) Peptide 356Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Pip(SEQ. ID. NO. 356) Peptide 361Lys-Leu-Lys-Gln-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 361) Peptide 363Lys-Lys-Leu-Gln-Leu-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Pip(SEQ. ID. NO. 363) Peptide 364Lys-Lys-Leu-Gln-Ala-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-Pip(SEQ. ID. NO. 364) Peptide 365Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 365) Peptide 366Lys-Leu-Lys-Lys-Gln-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-Pip(SEQ. ID. NO. 366) Peptide 367Lys-Leu-Lys-Gln-Glu-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip(SEQ. ID. NO. 367) Peptide 437Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPip (SEQ. ID. NO. 437) Peptide 438Lys-Leu-Lys-Gln-Lys-Trp-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 438) Peptide 439Lys-Leu-Lys-Lys-Lys-Leu-Ala-Lys-Leu-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 439) Peptide 440Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Glu-Asn-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 440) Peptide 441Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-(D-Val)-azPip (SEQ. ID. NO. 441) Peptide 442Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-azPip (SEQ. ID. NO. 442) Peptide 443Lys-Lys-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 443) Peptide 444Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 444) Peptide 445Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-azPip (SEQ. ID. NO. 445) Peptide 446Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asn-Leu-Leu-Glu-Asp-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 446) Peptide 448Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-azPip(SEQ. ID. NO. 448) Peptide 453Lys-Leu-Lys-Gln-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 453) Peptide 455Lys-Lys-Leu-Gln-Leu-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-azPip (SEQ. ID. NO. 455) Peptide 456Lys-Lys-Leu-Gln-Ala-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Ala-Asp-Leu-Val-azPip (SEQ. ID. NO. 456) Peptide 457Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 457) Peptide 458Lys-Leu-Lys-Lys-Gln-Leu-Asp-Glu-Leu-Leu-Arg-Glu-Phe-Leu-Glu-Leu-Val-azPip (SEQ. ID. NO. 458) Peptide 459Lys-Leu-Lys-Gln-Glu-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip (SEQ. ID. NO. 459)or a pharmaceutically acceptable salt thereof.

Some illustrative ApoA-I Mimics having an acetylated N-terminus and anamidated C-terminus are set forth in Tables 8 and 9 below:

TABLE 8 Peptide 64H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 64) Peptide 65H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 65) Peptide 66H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 66) Peptide 67H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 67) Peptide 68H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 68) Peptide 69H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 69) Peptide 70H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 70) Peptide 71H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 71) Peptide 72H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 72) Peptide 73H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 73) Peptide 74H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 74) Peptide 75H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 75) Peptide 76H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 76) Peptide 77H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 77) Peptide 78H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 78) Peptide 79H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 79) Peptide 80H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 80) Peptide 81H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 81) Peptide 82H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 82) Peptide 83H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 83) Peptide 84H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 84) Peptide 85H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 85) Peptide 86H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Gly-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 86) Peptide 87H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 87) Peptide 88H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 88) Peptide 89H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 89) Peptide 90H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 90) Peptide 91H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 91) Peptide 92H₃C(O)C-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 92) Peptide 93H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 93) Peptide 156H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 156) Peptide 157H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 157) Peptide 158H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 158) Peptide 159H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 159) Peptide 160H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 160) Peptide 161H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 161) Peptide 162H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 162) Peptide 163H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 163) Peptide 164H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 164) Prptide 165H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 165) Peptide 166H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 166) Peptide 167H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 167) Peptide 168H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 168) Peptide 169H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 169) Peptide 170H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 170) Peptide 171H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 171) Peptide 172H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 172) Peptide 173H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 173) Peptide 174H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 174) Peptide 175H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 175) Peptide 176H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 176) Peptide 177H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 177) Peptide 178H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Gly-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 178) Peptide 179H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 179) Peptide 180H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 180) Peptide 181H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 181) Peptide 182H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 182) Peptide 183H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 183) Peptide 184H₃C(O)C-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 184) Peptide 185H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 185) Peptide 276H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 276) Peptide 277H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 277) Peptide 278H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 278) Peptide 279H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 279) Peptide 280H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 280) Peptide 281H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 281) Peptide 282H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 282) Peptide 283H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 283) Peptide 284H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 284) Peptide 285H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 285) Peptide 286H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 286) Peptide 287H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 287) Peptide 288H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 288) Peptide 289H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 289) Peptide 290H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 290) Peptide 291H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 291) Peptide 292H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 292) Peptide 293H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 293) Peptide 294H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 294) Peptide 295H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 295) Peptide 296H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 296) Peptide 297H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 297) Peptide 298H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Gly-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 298) Peptide 299H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 299) Peptide 300H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 300) Peptide 301H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 301) Peptide 302H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 302) Peptide 303H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 303) Peptide 304H₃C(O)C-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 304) Peptide 305H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 305) Peptide 368H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 368) Peptide 369H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 369) Peptide 370H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 370) Peptide 371H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 371) Peptide 372H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 372) Peptide 373H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 373) Peptide 374H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 374) Peptide 375H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 375) Peptide 376H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 376) Peptide 377H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 377) Peptide 378H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 378) Peptide 379H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 379) Peptide 380H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 380) Peptide 381H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 381) Peptide 382H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 382) Peptide 383H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 383) Peptide 384H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 384) Peptide 385H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 385) Peptide 386H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 386) Peptide 387H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 387) Peptide 388H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 388) Peptide 389H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 389) Peptide 390H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Gly-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 390) Peptide 391H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 391) Peptide 392H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 392) Peptide 393H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 393) Peptide 394H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 394) Peptide 395H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 395) Peptide 396H₃C(O)C-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 396) Peptide 397H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 397) Peptide 460H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 460) Peptide 461H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 461) Peptide 462H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 462) Peptide 463H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 463) Peptide 464H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 464) Peptide 465H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 465) Peptide 466H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 466) Peptide 467H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 467) Peptide 468H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 468) Peptide 469H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 469) Peptide 470H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 470) Peptide 471H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 471) Peptide 472H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 472) Peptide 473H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 473) Peptide 474H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 474) Peptide 475H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 475) Peptide 476H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 476) Peptide 477H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 477) Peptide 478H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 478) Peptide 479H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 479) Peptide 480H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 480) Peptide 481H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 481) Peptide 482H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Gly-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 482) Peptide 483H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 483) Peptide 484H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 484) Peptide 485H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 485) Peptide 486H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 496) Peptide 487H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 487) Peptide 488H₃C(O)C-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 488) Peptide 489H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 489)or a pharmaceutically acceptable salt thereof.

TABLE 9 Peptide 65H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 65) Peptide 66H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 66) Peptide 67H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 67) Peptide 68H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 68) Peptide 69H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 69) Peptide 70H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 70) Peptide 71H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 71) Peptide 72H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 72) Peptide 73H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 73) Peptide 74H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 74) Peptide 75H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 75) Peptide 76H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Trp-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 76) Peptide 77H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 77) Peptide 78H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 78) Peptide 79H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 79) Peptide 80H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 80) Peptide 81H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 81) Peptide 82H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂ (SEQ. ID. NO. 82) Peptide 83H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 83) Peptide 84H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 84) Peptide 87H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Inp-NH₂ (SEQ. ID. NO. 87) Peptide 88H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 88) Peptide 89H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 89) Peptide 90H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 90) Peptide 91H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 91) Peptide 93H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂ (SEQ. ID. NO. 93) Peptide 157H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 157) Peptide 158H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 158) Peptide 159H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 159) Peptide 160H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 160) Peptide 161H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 161) Peptide 162H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 162) Peptide 163H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 163) Peptide 164H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 164) Peptide 165H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 165) Peptide 166H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 166) Peptide 167H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 167) Peptide 168H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 168) Peptide 169H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 169) Peptide 170H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 170) Peptide 171H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 171) Peptide 172H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 172) Peptide 173H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂ (SEQ. ID. NO. 173) Peptide 174H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 174) Peptide 175H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 175) Peptide 176H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 176) Peptide 179H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Nip-NH₂ (SEQ. ID. NO. 179) Peptide 180H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 180) Peptide 181H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 181) Peptide 182H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 182) Peptide 183H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 183) Peptide 185H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂ (SEQ. ID. NO. 185) Peptide 277H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 277) Peptide 278H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 278) Peptide 279H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 279) Peptide 280H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 280) Peptide 281H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 281) Peptide 282H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 282) Peptide 283H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 283) Peptide 284H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 284) Peptide 285H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 285) Peptide 286H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 286) Peptide 287H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 287) Peptide 288H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 288) Peptide 289H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 289) Peptide 290H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 290) Peptide 291H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 291) Peptide 292H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 292) Peptide 293H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPro-NH₂ (SEQ. ID. NO. 293) Peptide 294H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 294) Peptide 295H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 295) Peptide 296H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 296) Peptide 299H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPro-NH₂ (SEQ. ID. NO. 299) Peptide 300H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 300) Peptide 301H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 301) Peptide 302H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 302) Peptide 303H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 303) Peptide 305H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPro-NH₂ (SEQ. ID. NO. 305) Peptide 369H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 369) Peptide 370H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 370) Peptide 371H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 371) Peptide 372H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 372) Peptide 373H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 373) Peptide 374H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 374) Peptide 375H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 375) Peptide 376H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 376) Peptide 377H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 377) Peptide 378H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 378) Peptide 379H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 379) Peptide 380H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 380) Peptide 381H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 381) Peptide 382H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 382) Peptide 383H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 383) Peptide 384H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 384) Peptide 385H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Pip-NH₂ (SEQ. ID. NO. 385) Peptide 386H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 386) Peptide 387H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 387) Peptide 388H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 388) Peptide 391H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Pip-NH₂ (SEQ. ID. NO. 391) Peptide 392H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 392) Peptide 393H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 393) Peptide 394H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 394) Peptide 395H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 395) Peptide 397H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Pip-NH₂ (SEQ. ID. NO. 397) Peptide 461H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 461) Peptide 462H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 462) Peptide 463H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 463) Peptide 464H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 464) Peptide 465H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 465) Peptide 466H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 466) Peptide 467H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 467) Peptide 468H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 468) Peptide 469H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 469) Peptide 470H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 470) Peptide 471H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 471) Peptide 472H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 472) Peptide 473H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 473) Peptide 474H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 474) Peptide 475H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 475) Peptide 476H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 476) Peptide 477H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-azPip-NH₂ (SEQ. ID. NO. 477) Peptide 478H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 478) Peptide 479H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 479) Peptide 480H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 480) Peptide 483H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-azPip-NH₂ (SEQ. ID. NO. 483) Peptide 484H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 484) Peptide 385H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 485) Peptide 486H₃C(O)C-Lys-Gln-Lys-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 496) Peptide 487H₃C(O)C-Lys-Gln-Leu-Lys-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 487) Peptide 489H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-azPip-NH₂ (SEQ. ID. NO. 489)or a pharmaceutically acceptable salt thereof.

III. Synthesis of the ApoA-I Mimics

The ApoA-I Mimics can be prepared using virtually any art-knowntechnique for the preparation of peptides. For example, the ApoA-IMimics can be prepared using conventional step-wise solution or solidphase peptide syntheses, or recombinant DNA techniques.

A. Chemical Synthesis

The ApoA-I Mimics can be prepared using conventional step-wise solutionor solid phase synthesis (see, e.g., Chemical Approaches to theSynthesis of Peptides and Proteins, Williams et al., Eds., 1997, CRCPress, Boca Raton Fla., and references cited therein; Solid PhasePeptide Synthesis: A Practical Approach, Atherton & Sheppard, Eds.,1989, IRL Press, Oxford, England, and references cited therein).

Alternatively, the ApoA-I Mimics can be prepared by way of segmentcondensation, as described, for example, in Liu et al., 1996,Tetrahedron Lett. 37(7):933-936; Baca, et al., 1995, J. Am. Chem. Soc.117:1881-1887; Tam et al., 1995, Int. J. Peptide Protein Res.45:209-216; Schnolzer and Kent, 1992, Science 256:221-225; Liu and Tam,1994, J. Am. Chem. Soc. 116(10):4149-4153; Liu and Tam, 1994, Proc.Natl. Acad. Sci. USA 91:6584-6588; Yamashiro and Li, 1988, Int. J.Peptide Protein Res. 31:322-334). This is particularly the case withpeptides having a glycine residue. Other methods useful for synthesizingthe ApoA-I Mimics are described in Nakagawa et al., 1985, J. Am. Chem.Soc. 107:7087-7092.

ApoA-I Mimics having N- and/or C-terminal capping groups can be preparedusing standard techniques of organic chemistry. For example, methods foracylating the N-terminus of a peptide or amidating or esterifying theC-terminus of a peptide are well-known in the art. Modes of carryingother modifications at the N- and/or C-terminus will be apparent tothose of skill in the art, as will modes of protecting any side-chainfunctionalities as can be necessary to attach terminal blocking groups.

Pharmaceutically acceptable salts (counter ions) can be convenientlyprepared by ion-exchange chromatography or other methods as are wellknown in the art.

ApoA-I Mimics that are in the form of tandem multimers can beconveniently synthesized by adding the linker(s) to the peptide chain atthe appropriate step in the synthesis. Alternatively, the helicalsegments can be synthesized and each segment reacted with the linker. Ofcourse, the actual method of synthesis will depend on the composition ofthe linker. Suitable protecting schemes and chemistries are well known,and will be apparent to those of skill in the art.

ApoA-I Mimics that are in the form of branched networks can beconveniently synthesized using the trimeric and tetrameric resins andchemistries described in Tam, 1988, Proc. Natl. Acad. Sci. USA85:5409-5413 and Demoor et al., 1996, Eur. J. Biochem. 239:74-84.Modifying the synthetic resins and strategies to synthesize branchednetworks of higher or lower order, or which contain combinations ofdifferent ApoA-I Mimic helical segments, is well within the capabilitiesof those of skill in the art of peptide chemistry and/or organicchemistry.

Formation of disulfide linkages, if desired, can be conducted in thepresence of mild oxidizing agents. Chemical oxidizing agents can beused, or the ApoA-I Mimics can simply be exposed to atmospheric oxygento effect these linkages. Various methods are known in the art,including those described, for example, by Tam et al., 1979, Synthesis955-957; Stewart et al., 1984, Solid Phase Peptide Synthesis, 2d Ed.,Pierce Chemical Company Rockford, Ill.; Ahmed et al., 1975, J. Biol.Chem. 250:8477-8482; and Pennington et al., 1991 Peptides 1990 164-166,Giralt and Andreu, Eds., ESCOM Leiden, The Netherlands. An additionalalternative is described by Kamber et al., 1980, Helv. Chim. Acta63:899-915. A method conducted on solid supports is described byAlbericio, 1985, Int. J. Peptide Protein Res. 26:92-97. Any of thesemethods can be used to form disulfide linkages in the peptides of theinvention.

ApoA-I Mimics having one or more internal glycine residues can besynthesized in relatively high yield by way of segment condensation,thereby providing advantages for large-scale production. Segmentcondensation, i.e., the joining together of small constituent peptidechains to form a larger peptide chain, has been used to prepare manybiologically active peptides, including 44-amino acid residue mimics ofApoA-I (see, e.g., Nakagawa et al., 1985, J. Am. Chem. Soc.107:7087-7083; Nokihara et al., 1989, Peptides 1988:166-168;Kneib-Cordonnier et al., 1990, Int. J. Pept. Protein Res. 35:527-538).

Advantages of synthesis via segment condensation include the ability tocondense pre-formed segments in the solution phase and the ease ofpurification of the final product. Drawbacks of the method include lowcoupling efficiency and yield at the condensation step and lowsolubility of certain peptide sequences. The coupling efficiency of thecondensation step can be increased by increasing the coupling time.Typically, increasing the coupling time results in increasedracemezation of the product (Sieber et al., 1970, Helv. Chim. Acta53:2135-2150). However, since glycine lacks a chiral center it does notundergo racemezation (proline residues, due to steric hindrance, alsoundergo little or no racemezation at long coupling times). Thus,embodiments containing internal glycine residues can be synthesized inbulk in high yield via segment condensation by synthesizing constituentsegments which take advantage of the fact that glycine residues do notundergo racemezation. Thus, ApoA-I Mimics having one or more internalglycine residues provide synthetic advantages for large-scale bulkpreparation.

B. Recombinant Synthesis

If the ApoA-I Mimic is composed entirely of genetically-encoded aminoacid residues, or a portion of it is so composed, the ApoA-I Mimic orthe relevant portion can also be synthesized using conventionalrecombinant genetic engineering techniques.

For recombinant production, a polynucleotide sequence encoding thepeptide is inserted into an appropriate expression vehicle, i.e., avector which contains the necessary elements for the transcription andtranslation of the inserted coding sequence, or in the case of an RNAviral vector, the necessary elements for replication and translation.The expression vehicle is then transfected into a suitable target cellwhich will express the peptide. Depending on the expression system used,the expressed peptide is then isolated by procedures well-established inthe art. Methods for recombinant protein and peptide production are wellknown in the art (see, e.g., Sambrook et al., 1989, Molecular Cloning ALaboratory Manual, Cold Spring Harbor Laboratory, N.Y.; and Ausubel etal., 1989, Current Protocols in Molecular Biology, Greene PublishingAssociates and Wiley Interscience, N.Y. each of which is incorporated byreference herein in its entirety.)

To increase efficiency of production, the polynucleotide can be designedto encode multiple units of the peptide separated by enzymatic cleavagesites—either homopolymers (repeating peptide units) or heteropolymers(different peptides strung together) can be engineered in this way. Theresulting polypeptide can be cleaved (e.g., by treatment with theappropriate enzyme) in order to recover the peptide units. This canincrease the yield of peptides driven by a single promoter. In oneembodiment, a polycistronic polynucleotide can be designed so that asingle mRNA is transcribed which encodes multiple peptides (i.e.,homopolymers or heteropolymers) each coding region operatively linked toa cap-independent translation control sequence; e.g., an internalribosome entry site (IRES). When used in appropriate viral expressionsystems, the translation of each peptide encoded by the mRNA is directedinternally in the transcript; e.g., by the IRES. Thus, the polycistronicconstruct directs the transcription of a single, large polycistronicmRNA which, in turn, directs the translation of multiple, individualpeptides. This approach eliminates the production and enzymaticprocessing of polyproteins and can significantly increase yield ofpeptide driven by a single promoter.

A variety of host-expression vector systems can be utilized to expressthe ApoA-I Mimics. These include, but are not limited to, microorganismssuch as bacteria transformed with recombinant bacteriophage DNA orplasmid DNA expression vectors containing an appropriate codingsequence; yeast or filamentous fungi transformed with recombinant yeastor fungi expression vectors containing an appropriate coding sequence;insect cell systems infected with recombinant virus expression vectors(e.g., baculovirus) containing an appropriate coding sequence; plantcell systems infected with recombinant virus expression vectors (e.g.,cauliflower mosaic virus or tobacco mosaic virus) or transformed withrecombinant plasmid expression vectors (e.g., Ti plasmid) containing anappropriate coding sequence; or animal cell systems.

The expression elements of the expression systems can vary in theirstrength and specificities. Depending on the host/vector systemutilized, any of a number of suitable transcription and translationelements, including constitutive and inducible promoters, can be used inthe expression vector. For example, when cloning in bacterial systems,inducible promoters such as pL of bacteriophage λ, plac, ptrp, ptac(ptrp-lac hybrid promoter) and the like can be used; when cloning ininsect cell systems, promoters such as the baculovirus polyhedronpromoter can be used; when cloning in plant cell systems, promotersderived from the genome of plant cells (e.g., heat shock promoters; thepromoter for the small subunit of RUBISCO; the promoter for thechlorophyll a/b binding protein) or from plant viruses (e.g., the 35SRNA promoter of CaMV; the coat protein promoter of TMV) can be used;when cloning in mammalian cell systems, promoters derived from thegenome of mammalian cells (e.g., metallothionein promoter) or frommammalian viruses (e.g., the adenovirus late promoter; the vacciniavirus 7.5 K promoter) can be used; when generating cell lines thatcontain multiple copies of expression product, SV40-, BPV- and EBV-basedvectors can be used with an appropriate selectable marker.

In cases where plant expression vectors are used, the expression ofsequences encoding the ApoA-I Mimics can be driven by any of a number ofpromoters. For example, viral promoters such as the 35S RNA and 19S RNApromoters of CaMV (Brisson et al., 1984, Nature 310:511-514), or thecoat protein promoter of TMV (Takamatsu et al., 1987, EMBO J. 6:307-311)can be used; alternatively, plant promoters such as the small subunit ofRUBISCO (Coruzzi et al., 1984, EMBO J. 3:1671-1680; Broglie et al.,1984, Science 224:838-843) or heat shock promoters, e.g., soybeanhsp17.5-E or hsp17.3-B (Gurley et al., 1986, Mol. Cell. Biol. 6:559-565)can be used. These constructs can be introduced into plant cells usingTi plasmids, Ri plasmids, plant virus vectors, direct DNAtransformation, microinjection, electroporation, etc. For reviews ofsuch techniques see, e.g., Weissbach & Weissbach, 1988, Methods forPlant Molecular Biology, Academic Press, N.Y., Section VIII, pp.421-463; and Grierson & Corey, 1988, Plant Molecular Biology, 2d Ed.,Blackie, London, Ch. 7-9.

In one insect expression system that can be used to produce the ApoA-IMimics, Autographa californica, nuclear polyhidrosis virus (AcNPV) isused as a vector to express the foreign genes. The virus grows inSpodoptera frugiperda cells. A coding sequence can be cloned intonon-essential regions (for example the polyhedron gene) of the virus andplaced under control of an AcNPV promoter (for example, the polyhedronpromoter). Successful insertion of a coding sequence will result ininactivation of the polyhedron gene and production of non-occludedrecombinant virus (i.e., virus lacking the proteinaceous coat coded forby the polyhedron gene). These recombinant viruses are then used toinfect Spodoptera frugiperda cells in which the inserted gene isexpressed (e.g., see Smith et al., 1983, J. Virol. 46:584; Smith, U.S.Pat. No. 4,215,051). Further examples of this expression system can befound in Current Protocols in Molecular Biology, Vol. 2, Ausubel et al.,eds., Greene Publish. Assoc. & Wiley Interscience.

In mammalian host cells, a number of viral-based expression systems canbe utilized. In cases where an adenovirus is used as an expressionvector, a coding sequence can be ligated to an adenovirustranscription/translation control complex, e.g., the late promoter andtripartite leader sequence. This chimeric gene can then be inserted inthe adenovirus genome by in vitro or in vivo recombination. Insertion ina non-essential region of the viral genome (e.g., region E1 or E3) willresult in a recombinant virus that is viable and capable of expressingpeptide in infected hosts. (e.g., See Logan & Shenk, 1984, Proc. Natl.Acad. Sci. (USA) 81:3655-3659). Alternatively, the vaccinia 7.5 Kpromoter can be used, (see, e.g., Mackett et al., 1982, Proc. Natl.Acad. Sci. (USA) 79:7415-7419; Mackett et al., 1984, J. Virol.49:857-864; Panicali et al., 1982, Proc. Natl. Acad. Sci. 79:4927-4931).

Other expression systems for producing the ApoA-I Mimics will beapparent to those having skill in the art.

C. Purification

The ApoA-I Mimics can be purified by art-known techniques such asreverse phase chromatography, high performance liquid chromatography,ion exchange chromatography, gel electrophoresis, affinitychromatography and the like. The actual conditions used to purify aparticular ApoA-I Mimic can depend, in part, on synthesis strategy andon factors such as net charge, hydrophobicity, hydrophilicity, etc., andwill be apparent to those having skill in the art. Multimeric branchedpeptides can be purified, e.g., by ion exchange or size exclusionchromatography.

For affinity chromatography purification, any antibody whichspecifically binds the ApoA-I Mimic can be used. For the production ofantibodies, various host animals, including but not limited to rabbits,mice, rats, etc., can be immunized by injection with a peptide. Thepeptide can be attached to a suitable carrier, such as BSA, by means ofa side chain functional group or linkers attached to a side chainfunctional group. Various adjuvants can be used to increase theimmunological response, depending on the host species, including but notlimited to Freund's (complete and incomplete), mineral gels such asaluminum hydroxide, surface active substances such as lysolecithin,pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpethemocyanin, dinitrophenol, and potentially useful human adjuvants suchas BCG (bacilli Calmette-Guerin) and Corynebacterium parvum.

Monoclonal antibodies to an ApoA-I Mimic can be prepared using anytechnique which provides for the production of antibody molecules bycontinuous cell lines in culture. These include but are not limited tothe hybridoma technique described by Kohler and Milstein, 1975, Nature256:495-497, or Kaprowski, U.S. Pat. No. 4,376,110 which is incorporatedby reference herein; the human B-cell hybridoma technique) Kosbor etal., 1983, Immunology Today 4:72; Cote et al., 1983, Proc. Natl. Acad.Sci. U.S.A. 80:2026-2030); and the EBV-hybridoma technique (Cole et al.,1985, Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp.77-96 (1985)). In addition, techniques developed for the production of“chimeric antibodies” Morrison et al., 1984, Proc. Natl. Acad. Sci.U.S.A. 81:6851-6855; Neuberger et al., 1984, Nature 312:604-608; Takedaet al., 1985, Nature 314:452-454, Boss, U.S. Pat. No. 4,816,397;Cabilly, U.S. Pat. No. 4,816,567; which are incorporated by referenceherein) by splicing the genes from a mouse antibody molecule ofappropriate antigen specificity together with genes from a humanantibody molecule of appropriate biological activity can be used. Or“humanized” antibodies can be prepared (see, e.g., Queen, U.S. Pat. No.5,585,089 which is incorporated by reference herein). Alternatively,techniques described for the production of single chain antibodies (U.S.Pat. No. 4,946,778) can be adapted to produce peptide-specific singlechain antibodies.

Antibody fragments which contain deletions of specific binding sites canbe generated by known techniques. For example, such fragments includebut are not limited to F(ab′)₂ fragments, which can be produced bypepsin digestion of the antibody molecule and Fab fragments, which canbe generated by reducing the disulfide bridges of the F(ab′)₂ fragments.Alternatively, Fab expression libraries can be constructed (Huse et al.,1989, Science 246:1275-1281) to allow rapid and easy identification ofmonoclonal Fab fragments with the desired specificity for the peptide ofinterest.

The antibody or antibody fragment specific for the desired ApoA-I Mimiccan be attached, for example, to agarose, and the antibody-agarosecomplex is used in immunochromatography to purify peptides of theinvention. See, Scopes, 1984, Protein Purification: Principles andPractice, Springer-Verlag New York, Inc., N.Y., Livingstone, 1974,Methods In Enzymology: Immunoaffinity Chromatography of Proteins34:723-731.

IV. Compositions

In one embodiment, the invention provides compositions comprising aneffective amount of an ApoA-I Mimic and a pharmaceutically acceptablecarrier or vehicle.

The compositions can be formulated for administration to a mammal byinjection. Injectable preparations include sterile suspensions,solutions or emulsions of the active ingredient in aqueous or oilyvehicles. The compositions can also comprise formulating agents, such assuspending, stabilizing and/or dispersing agent. The formulations forinjection can be presented in unit dosage form, e.g., in ampules or inmultidose containers, and can contain added preservatives.Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, an ApoA-I Mimic can be lyophilized, or a co-lyophilizedpeptide-lipid complex can be prepared. The stored preparations can besupplied in unit dosage forms and reconstituted prior to use in vivo.

For prolonged delivery, the composition can be formulated as a depotpreparation, for administration by implantation; e.g., subcutaneous,intradermal, or intramuscular injection. Thus, for example, the ApoA-IMimic can be formulated with suitable polymeric or hydrophobic materials(e.g., as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives; e.g., as a sparingly soluble salt formof the ApoA-I Mimic.

In other embodiment, the compositions are administered intravenously.Alternatively, transdermal delivery systems manufactured as an adhesivedisc or patch which slowly releases the active ingredient forpercutaneous absorption can be used. To this end, permeation enhancerscan be used to facilitate transdermal penetration of the ApoA-I Mimic. Aparticular benefit can be achieved by incorporating the ApoA-I Mimicinto a nitroglycerin patch for use in a mammal having a Condition suchas ischemic heart disease or hypercholesterolemia.

For oral administration, the compositions can take the form of, forexample, tablets or capsules prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talcor silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulfate). The tabletscan be coated by methods well known in the art. Liquid preparations fororal administration can take the form of, for example, solutions, syrupsor suspensions, or they can be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations can be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations can also contain buffer salts, flavoring,coloring and sweetening agents as appropriate. Preparations for oraladministration can be suitably formulated to give controlled release ofthe ApoA-I Mimic.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in conventional manner. For rectal and vaginalroutes of administration, the active ingredient can be formulated assolutions (for retention enemas) suppositories or ointments.

For administration by inhalation, the ApoA-I Mimic can be convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g. gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the ApoA-I Mimic and a suitable powder basesuch as lactose or starch.

The compositions can, if desired, be presented in a pack or dispenserdevice which can contain one or more unit dosage forms containing theApoA-I Mimic. The pack can for example comprise metal or plastic foil,such as a blister pack. The pack or dispenser device can be accompaniedby instructions for administration.

In some embodiments, one can formulate or administer the ApoA-I Mimic asa complex with a lipid. Accordingly, the invention includes ApoA-IMimic/lipid complexes, compositions thereof, and methods for theiradministration. The complexes can have several advantages since they canhave an increased half-life in the circulation, particularly when thecomplex has a similar size and density to HDL, and especially thepre-β-1 or pre-β-2 HDL populations. The complexes can be conveniently beprepared using any of a number of methods described below. Stablepreparations having a relatively long shelf life can be made bylyophilization, —the co-lyophilization procedure described below beingone embodiment. The lyophilized complexes can be used to prepare bulkfor pharmaceutical reformulation, or to prepare individual aliquots ordosage units which can be reconstituted by rehydration with sterilewater or an appropriate buffered solution prior to administration to asubject.

A variety of methods well known to those skilled in the art can be usedto prepare the complexes. For example, a number of available techniquesfor preparing liposomes or proteoliposomes can be used. For example, theApoA-I Mimic can be cosonicated (using a bath or probe sonicator) withappropriate lipids to form complexes. Alternatively the ApoA-I Mimic canbe combined with preformed lipid vesicles resulting in the spontaneousformation of peptide-lipid complexes. In yet another alternative, thecomplexes can be formed by a detergent dialysis method; e.g., a mixtureof the ApoA-I Mimic, lipid and detergent is dialyzed to remove thedetergent and reconstitute or form complexes (see, e.g., Jonas et al.,1986, Methods in Enzymol. 128:553-582).

Alternatively, the complexes can be prepared by the methods disclosed inU.S. Pat. No. 6,004,925 (“'925 patent”), the entire disclosure of whichis herein incorporated by reference. In the methods of the '925 patent,the ApoA-I Mimic and lipid are combined in a solvent system whichco-solubilizes each ingredient and which can be completely removed bylyophilization. To this end, solvent pairs are selected to ensureco-solubility of both the ApoA-I Mimic and the lipid. In one embodiment,the ApoA-I Mimic of the complex can be dissolved in an aqueous ororganic solvent or mixture of solvents (solvent 1). The lipid, such as aphospholipid, component is dissolved in an aqueous or organic solvent ormixture of solvents (solvent 2) which is miscible with solvent 1, andthe two solutions are mixed. Alternatively, the ApoA-I Mimic and lipidcan be incorporated into a co-solvent system; i.e., a mixture of themiscible solvents. Alternatively, the ApoA-I Mimic and lipid can besuspended in a solvent or mixture of solvents. In one embodiment, themixture of solvents is a mixture of organic solvent and water. Examplesof organic solvents include, but are not limited to, acetic acid,xylene, cyclohexane, and methanol. Examples of solvent mixtures include,but are not limited to, acetic acid and xylene, acetic acid andcyclohexane, and methanol and xylene. A suitable proportion of ApoA-IMimic to lipids can be first determined empirically so that theresultant complexes possess the appropriate physical and chemicalproperties; i.e., usually (but not necessarily) similar in size to HDL.The resultant mixture is frozen and lyophilized to dryness. Sometimes anadditional solvent is added to the mixture to facilitate lyophilization.This lyophilized product may be stored for long periods and willtypically remain stable.

Alternatively, the complexes can be prepared by co-lyophilization of theApoA-I Mimic with peptide in solutions or suspensions. The homogeneoussolution of peptide and phospholipids of choice in an organic solvent ororganic solvent mixture can be lyophilized, and peptide/phospholipidcomplexes can be formed spontaneously by hydration of the lyophilizedpowder with an aqueous buffer.

The lyophilized product may be reconstituted in order to obtain asolution or suspension of the complex. To this end, the lyophilizedpowder is rehydrated with an aqueous solution to a suitable volume(often 5-20 mg peptide/mL which is convenient for intravenousinjection). In one embodiment, the lyophilized powder is rehydrated withphosphate buffered saline, saline bicarbonate, or a physiological salinesolution. The pH of the mixture can be adjusted to 7.5-8.5. The mixturecan be agitated or vortexed to facilitate rehydration, and in mostcases, the reconstitution step can be conducted at a temperature equalto or greater than the phase transition temperature of the lipidcomponent of the complexes. Within minutes, a clear preparation ofreconstituted lipid-protein complexes results.

An aliquot of the resultant reconstituted preparation can becharacterized to confirm that the complexes in the preparation have thedesired size distribution; e.g., the size distribution of HDL.Characterization of the reconstituted preparation can be performed usingany method known in the art, including, but not limited to, sizeexclusion filtration chromatography, gel filtration chromatography,column filtration chromatography, gel permeation chromatography, andnative page electrophoresis. In one embodiment, the reconstitutedpreparation is characterized by gel filtration chromatography. The sizeof the resultant complexes may be determinative of their efficacy. Inthe examples described below, a Pharmacia Superose 6 FPLC gel filtrationchromatography system is used. The buffer that is used contains 150 mMNaCl in 50 mM phosphate buffer, pH about 7.0 to about 9, in oneembodiment 7.5-8.5, in another embodiment 7.4. A typical sample volumeis 20 to 200 microliters of complexes containing 5 mg peptide/mL. Thecolumn flow rate is 0.5 mL/min. A series of proteins of known molecularweight and Stokes's diameter as well as human HDL are used as standardsto calibrate the column. The proteins and lipoprotein complexes aremonitored by absorbance or scattering of light of wavelength 254 or 280nm.

The reconstituted preparation can also be characterized to determine theconcentration, final pH and osmolality of resulting solution, as well asthe concentration and integrities of peptide and individual lipids.ApoA-I Mimic and lipid concentration of the complexes can be measured byany method known in the art, including, but not limited to, protein andphospholipid assays, and chromatographic methods such as highperformance liquid chromatography (“HPLC”), gel filtrationchromatography, gas chromatography (“GC”). The chromatographs can becoupled with various detectors including, but not limited to, massspectrometers, UV or diode-array, fluorescent, and elastic lightscattering detectors. The integrity of the ApoA-I Mimic and lipid in thecomplexes can be determined by the chromatographic techniques describedabove, as well as by amino acid analysis, thin layer chromatography, andstandard assays to determine lipid oxidation for lipids.

The lipid of the ApoA-I Mimic/lipid complex can be one or more of avariety of lipids, including, but not limited to, saturated,unsaturated, natural and synthetic lipids and phospholipids, andpharmaceutically acceptable salts thereof. Typical salts include, butare not limited to, sodium, calcium, magnesium, and potassium salts.

Suitable lipids of the ApoA-I Mimic/lipid complexes include, but are notlimited to, (C₁-C₆) alkyl chain phospholipids, phosphatidylcholine (PC),egg phosphatidylcholine, soybean phosphatidylcholine,dipalmitoylphosphatidylcholine, dimyristoylphosphatidylcholine,distearoylphosphatidylcholine1-myristoyl-2-palmitoylphosphatidylcholine,1-palmitoyl-2-myristoylphosphatidylcholine,1-palmitoyl-2-stearoylphosphatidylcholine,1-stearoyl-2-palmitoylphosphatidylcholine,1-palmitoyl-2-oleoylphosphatidylcholine,1-oleoyl-2-palmitylphosphatidylcholine, dioleoylphosphatidylcholine,dioleoylphosphatidylethanolamine, dilauroylphosphatidylglycerolphosphatidylcholine, phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, sphingomyelin, sphingolipids,phosphatidylglycerol, diphosphatidylglycerol,dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol,distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol,dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid,dimyristoylphosphatidylethanolamine,dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine,dipalmitoylphosphatidylserine, brain phosphatidylserine, sphingomyelin,brain sphingomyelin, dipalmitoylsphingomyelin, distearoylsphingomyelin,phosphatidic acid, galactocerebroside, gangliosides, cerebrosides,dilaurylphosphatidylcholine, (1,3)-D-mannosyl-(1,3)diglyceride,aminophenylglycoside, 3-cholesteryl-6′-(glycosylthio)hexyl etherglycolipids, and cholesterol and its derivatives.

In one embodiment, the lipid of the ApoA-I Mimic/lipid complex is aneutral phospholipid. The neutral phospholipid can be any phospholipidthat has a net charge of about zero at physiological pH. In someembodiments, the neutral phospholipid is a zwitterion that has a netcharge of about zero at physiological pH.

In another embodiment, the neutral phospholipid is a lecithin (alsoknown as phosphatidylcholine). In some embodiments, the neutralphospholipid is a mixture of neutral phospholipids that comprises about5 to about 100 wt % lecithin. In other embodiments, the mixture ofneutral phospholipids comprises about 100 wt % lecithin. In someembodiments, the neutral phospholipid is a mixture of neutralphospholipids that comprises about 5 to about 100 mole % lecithin. Inother embodiments, the mixture of neutral phospholipids comprises about100 mole % lecithin.

In another embodiment, the neutral phospholipid is a sphingomyelin. Insome embodiments, the neutral phospholipid is a mixture of neutralphospholipids that comprises about 5 to about 100 wt % sphingomyelin. Inother embodiments, the neutral phospholipid is a mixture of neutralphospholipids that comprises about 100 wt % sphingomyelin. In someembodiments, the neutral phospholipid is a mixture of neutralphospholipids that comprises about 5 to about 100 mole % sphingomyelin.In other embodiments, the neutral phospholipid is a mixture of neutralphospholipids that comprises about 100 mole % sphingomyelin.

In another embodiment, the neutral phospholipid of the ApoA-IMimic/lipid complex is a mixture of neutral phospholipids that comprisesa lecithin and a sphingomyelin. The molar ratio of lecithin tosphingomyelin can vary, but typically ranges from about 20:about 1 toabout 1:about 20. In some embodiments, the lecithin:sphingomyelin molarratio ranges from about 10:about 3 to about 10:about 6. In otherembodiments, the lecithin:sphingomyelin molar ratio ranges from about1:about 20 to about 3:about 10.

In another embodiment, the neutral phospholipid of the ApoA-IMimic/lipid complex is a mixture of neutral phospholipids that compriseslechitin, sphingomyelin and one or more additional neutralphospholipids. Typically, the additional neutral phospholipid comprisesfrom about 5 to about 100 wt % of the mixture.

In another embodiment, the lipid of the ApoA-I Mimic/lipid complex is acharged phospholipid. Suitable charged phospholipids include, but arenot limited to, phosphatidylinositol, phosphatidylserine,phosphatidylglycerol and phosphatidic acid.

In one embodiment, the lipid of the ApoA-I Mimic/lipid complex is amixture of at least one neutral phospholipid and at least one chargedphospholipid. The total amount of charged phospholipids(s) in the lipidmixture can vary, but typically ranges from about 0.2 to about 10 wt %of the lipid mixture. In some embodiments, the total amount of chargedphospholipids(s) in the lipid mixture is about 0.2 to about 2 wt %,about 0.2 to about 3 wt %, about 0.2 to about 4 wt %, about 0.2 to about5 wt %, about 0.2 to about 6 wt %, about 0.2 to about 7 wt %, about 0.2to about 8 wt % or about 0.2 to about 9 wt % of the lipid mixture. Insome embodiments, the total amount of charged phospholipids(s) in thelipid mixture is about 0.2, about 0.3, about 0.4, about 0.5, about 0.6,about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9,about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about2.6, about 2.7, about 2.8, about 2.9 or about 3.0, about 4, about 5,about 6, about 7, about 8, about 9, or about 10 wt % of the lipidmixture. The total amount of neutral phospholipid(s) in the lipidmixture can also vary, and can depend upon the amount of chargedphospholipid(s) and any other lipids included. In one embodiment, thetotal amount of neutral phospholipids(s) in the lipid mixture is about90 to 99.8 wt % of the lipid mixture. In one embodiment, the lipid ofthe ApoA-I Mimic/lipid complex is a mixture of sphingomyelin and acharged phospholipid. In another embodiment, the lipid of the ApoA-IMimic/lipid complex is a mixture of sphingomyelin,dipalmitoylphosphatidylcholine (“DPPC”), and a charged phospholipid.

In one embodiment, the lipid of the ApoA-I Mimic/lipid complex issphingomyelin. In another embodiment, the spingomyelin is obtained frommilk, egg or brain or made synthetically. In another embodiment, thelipid of the ApoA-I Mimic/lipid complex is a sphingomyelin analog orderivative. Suitable sphingomyelin analogs or derivatives include, butare not limited to, palmitoylsphingomyelin, stearoylsphingomyelin,D-erythrose-sphingomyelin, and D-erythrose-dihydrosphingomyelin.

In another embodiment, the sphingomyelin is artificially enriched in oneparticular saturated or unsaturated acyl chain. For example, milksphingomyelin (Avanti Phospholipid, Alabaster, Ala.) has long saturatedacyl chains. Milk sphingomyelin comprises about 20% of C16:0 (16 carbon,saturated) acyl chain compared with egg sphingomyelin, which comprises80% of C16:0. Using solvent extraction, milk sphingomyelin can beenriched in one particular acyl chain to obtain a composition having anacyl chain concentration comparable with, e.g., egg sphingomyelin. Acylchains that may be utilized by the invention include, but are notlimited to saturated acyl chains (such as dipalmitoyl, distearoyl,diarachidonyl, and dibenzoyl acyl chains), unsaturated chains (such asdiolcoyl chains), mixed chains of saturated and unsaturated acyl chains(such as palmitoyl or oleoyl chains), saturated and/or unsaturatedchains of mixed lengths, and ether analogs of saturated and unsaturatedacyl chains.

The sphingomyelin may be semi-synthetic such that it has a particularacyl chain. For example, milk sphingomyelin can first be purified frommilk, then one particular acyl chain, e.g., the C16:0 acyl chain, can becleaved and replaced by another acyl chain (such as palmitic acid oroleic acid).

Sphingomyelin can also be entirely synthesized, by e.g., large-scalesynthesis. See, e.g., Dong et al, U.S. Pat. No. 5,220,043; Weis, 1999,Chem. Phys. Lipids 102(1-2):3-12. In one embodiment, a predefinedsaturation level and fatty acid composition is selected for thesynthetic sphingomyelin.

In another embodiment, the lipid of the ApoA-I Mimc/lipid complex is amixture of sphingomyelin and another lipid. In this embodiment, thesphingomyelin typically comprises from about 25 to about 75 wt % of themixture.

In another embodiment, the lipid of the ApoA-I Mimc/lipid complex is amixture of sphingomyelin and DPPC. In another embodiment, the lipid ofthe ApoA-I Mimic/lipid complex is a mixture of sphingomyelin, DPPC, anddipalmitoylphosphatidylglycerol (“DPPG”). In one embodiment, DPPG ispresent at about 0 to about 10% mole or weight % of the mixture. Inanother embodiment, DPPG is present at about 2 to about 4 mole or weight% of the mixture. In another embodiment, sphingomyelin and DPPG arepresent in the mixture in a weight or molar ratio of about 1:about 1. Inanother embodiment, the sphingomyelin, DPPC, and DPPG are present in aweight or molar ratio of about 1:about 1:about 0.06, respectively. Inanother embodiment, the sphingomyelin, DPPC, and DPPG are present in amolar ratio of 1.04:1:0.061, respectively. In another embodiment, thesphingomyelin, DPPC, and DPPG are present in a weight ratio of1:1:0.062, respectively. In another embodiment, the mixture is about48.5 mole or weight % sphingomyelin, about 48.5 mole or weight % DPPC,and about 3 mole or weight % DPPG.

In another embodiment, the ApoA-I Mimic/lipid complex comprises one ormore additional peptides. In one embodiment, the additional peptide isApoA-I.

In one embodiment, the weight ratio of total peptide to lipid in eachApoA-I Mimic/lipid complex is about 1:about 0.5 to about 1:about 5. Inanother embodiment, the weight ratio of total peptide to lipid in eachApoA-I Mimic/lipid complex is about 1:about 1 to about 1:about 5. Inanother embodiment, the weight ratio of total peptide to lipid in eachApoA-I Mimic/lipid complex is about 1:about 2 to about 1:about 5. Inanother embodiment, the weight ratio of total peptide to lipid in eachApoA-I Mimic/lipid complex is about 1:about 2.5. In another embodiment,the weight ratio of total peptide to lipid in each ApoA-I Mimic/lipidcomplex is about 1:about 3 to 1:about 5. In another embodiment, themolar ratio of total peptide to lipid in each ApoA-I Mimic/lipid complexis about 1:about 2.5 to about 1:about 20. In another embodiment, themolar ratio of total peptide to lipid in each ApoA-I mimic/lipid complexis about 1:about 9.2.

Where the lipid of the ApoA-I Mimic/lipid complex is a mixture ofsphingomyelin, DPPC, and DPPG, the peptide:sphingomyelin:DPPC:DPPGweight ratio is typically about 1:about 1:about 1:about 0.08,respectively. In one embodiment, the peptide:sphingomyelin:DPPC:DPPGweight ratio is 1:1.2125:1.2125:0.075, respectively. Thepeptide:sphingomyelin:DPPC:DPPG molar ratio is typically about 1:about4:about 4:about 0.03, respectively. In one embodiment, thepeptide:sphingomyelin:DPPC:DPPG molar ratio is 1:4.55:4.36:0.27,respectively.

In another embodiment, the ApoA-I Mimic/lipid complex comprises about 40to about 85 wt % lipid and about 15 to about 60 wt % peptide.

In another embodiment, each ApoA-I Mimic/lipid complex is about 2 toabout 12 nm in diameter.

V. Methods for Treating or Preventing a Condition

While not being bound by any particular theory, it is believed that thehelix formed by the ApoA-I Mimics of the invention closely mimics thestructural and functional properties of the amphipathic helical regionsof native ApoA-I that are important for effecting lipid-binding,cholesterol efflux, and/or LCAT activation, thereby resulting inpeptides that exhibit high ApoA-1-like activity. In one embodiment, theApoA-I Mimics function by forming amphipathic helices (in the presenceof lipids), binding lipids, forming pre-β-like or HDL-like complexes,activating LCAT, increasing serum HDL concentration and promotingcholesterol efflux.

In one embodiment, the ApoA-I Mimics activate LCAT. In anotherembodiment, the ApoA-I Mimics do not activate LCAT. In anotherembodiment, the ApoA-I Mimics activate LCAT, but only to a degree thatdoes not result in an acceleration of cholesterol esterification. Inanother embodiment, the ApoA-I Mimics activate LCAT, and therebyaccelerate cholesterol esterification, but wherein the acceleration ofcholesterol esterification due to LCAT activation, without more, isinsufficient to treat or prevent a Condition.

In one embodiment, the invention provides methods for treating orpreventing a Condition, comprising administering an effective amount ofan ApoA-I Mimic to a mammal in need thereof.

Examples of dyslipidemia include any disorder for which increasing serumHDL concentration, activating LCAT, and promoting cholesterol efflux andRCT is beneficial. Such disorders include, but are not limited to,hyperproteinemia (such as hyperchlyomicronemia), high low-densitylipoprotein serum concentration, high very low-density lipoprotein serumconcentration, hyperlipidemia (such as hypercholesterolemia orhyperglyceridemia (such as hypertriglyceridemia)), low high densitylipoprotein serum concentration, hypocholesterolemia,Abetalipoproteinemia, ApoA-I deficiency and Tangier disease.

Examples of cardiovascular disease include, but are not limited to,metabolic syndrome, ischemic heart disease, atherosclerosis, restenosis(e.g., preventing or treating atherosclerotic plaques which develop as aconsequence of medical procedures such as balloon angioplasty),endotoxemia (which often results in septic shock), congestive heartfailure (such as chronic or acute heart failure), circulatory shock,cardiomyopathy, cardiac transplant, myocardial infarction, a cardiacarrhythmia (such as atrial fibrillation), supraventricular tachycardia,atrial flutter, paroxysmal atrial tachycardia, aneurysm, angina,cerebrovascular accident (stroke), peripheral vascular disease,cerebrovascular disease, kidney disease, atherogenesis, therosclerosis,acute pancreatitis, and coronary artery disease.

Endothelial dysfunction is any imbalance between the vasodilating andvasoconstricting factors and growth-inhibiting and growth-promotingfactors produced by the endothelium. Endothelial dysfunction typicallyimpairs the blood vessels' ability to dilate.

Examples of macrovascular disorders include any disorder of a largeblood vessel. Such disorders include, but are not limited to, transientischaemic attack, stroke, angina, myocardial infarction, cardiacfailure, and peripheral vascular disease.

Examples of microvascular disorders include any disorder of a smallblood vessel. Such disorders include, but are not limited to, diabeticretinopathy (non-proliferative, proliferative, macular oedema),microalbuminuria, macroalbuminuria, end stage renal disease, erectiledysfunction, autonomic neuropathy, peripheral neuropathy, osteomyelitisand lower limb ischaemia.

The ApoA-I Mimics can be administered alone or in combination with oneor more other drugs that are useful for treating a Condition. Suchtherapies include, but are not limited to, simultaneous or sequentialadministration of the drugs involved.

In one embodiment, methods for treating or preventing a Condition canfurther comprise administering one or more drugs from one or more of thefollowing classes: ACE (angiotensin converting enzyme) inhibitors, betablockers, nitrates, calcium channel blockers, diuretics, thrombolyticagents, and blood cholesterol-lowering agents. In another embodiment,the methods of treating or preventing a Condition further compriseadministering one or more of: cholestyramine, colestipol, colesevelam,gemfibrozil, ciprofibrate, clofibrate, fenofibrate, bezafibrate,ezetimibe, ramipril, verapamil, nicardipine, diltiazem, carvedilol,nadolol, isosorbide mononitrate, propranolol, isosorbide dinitrate,digoxin, furosemide, metoprolol tartrate, trandolapril, nitroglycerin,amlodipine besylate, oxycodone, clopidogrel, nifedipine, atenolol,lisinopril, aspirin, and lanoxin.

In yet another embodiment, methods for treating or preventing aCondition can further comprise administering one or more of thecholesterol lowering drugs known to one of skill in the art; e.g.,bile-acid resins, niacin, and/or statins, such as atorvastatin,simvastatin, pravastatin, fluvastatin and pitavastatin. Such a regimenmay produce particularly beneficial therapeutic effects since each drugacts on a different target in cholesterol synthesis and transport; i.e.,bile-acid resins affect cholesterol recycling, the chylomicron and LDLpopulation; niacin primarily affects the VLDL and LDL population; thestatins inhibit cholesterol synthesis, decreasing the LDL population(and perhaps increasing LDL receptor expression); whereas the ApoA-IMimics affect RCT, increase HDL, increase LCAT activity and promotecholesterol efflux.

In another embodiment, methods for treating or preventing a Conditioncan further comprise administering a fibrate, such as clinofibrate,clofibrate, simfibrate, fenofibrate, and benzafibrate.

In yet another embodiment, methods for treating or preventing aCondition can further comprise administering an anti-microbial agentand/or an anti-inflammatory agent, for example, that is useful fortreating septic shock induced by endotoxin.

The ApoA-I Mimics can be administered by any suitable route that ensuresbioavailability in the circulation. This may be achieved by parenteralroutes of administration, including intravenous (IV), intramuscular(IM), intradermal, subcutaneous (SC) and intraperitoneal (IP)injections. However, other routes of administration can be used. Forexample, absorption through the gastrointestinal tract may beaccomplished by oral routes of administration (including but not limitedto ingestion, buccal and sublingual routes) provided appropriateformulations (e.g., enteric coatings) are used to avoid or minimizedegradation of the peptides, e.g., in the harsh environments of the oralmucosa, stomach and/or small intestine. Alternatively, administrationvia mucosal tissue such as vaginal and rectal modes of administrationmay be utilized to avoid or minimize degradation in the gastrointestinaltract. In yet another alternative, the formulations of the invention maybe administered transcutaneously (e.g., transdermally), ocularly, or byinhalation. It will be appreciated that the route of administrationchosen may vary with the condition, age and compliance of the recipient.

The actual dose of the ApoA-I Mimic used can vary with the route ofadministration, and can be adjusted to achieve circulating plasmaconcentrations of ApoA-I Mimic of 100 mg/L to 2 g/L. In one embodiment,the dose of ApoA-I Mimic is adjusted to achieve a serum level of free orcomplexed ApoA-I Mimic for at least 24 hours following administrationthat is in the range of about 10 mg/dL to 300 mg/dL higher than abaseline (initial) level prior to administration.

The ApoA-I Mimics may be administered in a variety of differenttreatment regimens. In one embodiment, the ApoA-I Mimic is administeredby injection at a dose between 0.5 mg/kg to 100 mg/kg once a week. Inanother embodiment, desirable serum levels may be maintained bycontinuous infusion or by intermittent infusion providing about 0.5mg/kg/hr to 100 mg/kg/hr of the ApoA-I Mimic. In one embodiment, theApoA-I Mimic is administered at a dose of about 20 mg/kg.

In another embodiment, the ApoA-I Mimc is administered by intravenousinjection once or more per day. In another embodiment, the ApoA-I Mimicis administered by injection once every 3 to 15 days, once every 5 to 10days, or once every 10 days. In another embodiment, the ApoA-I Mimic isadministered in a series of maintenance injections, where the series ofmaintenance injections is administered once every 6 months to one year.The series of maintenance injections can be administered, for example,over one day (perfusion to maintain a specified plasma level ofcomplexes), several days (e.g., four injections over a period of eightdays) or several weeks (e.g., four injections over a period of fourweeks).

In yet another embodiment, an escalating dose of ApoA-I Mimic can beadministered, starting with about 1 to 5 doses at amount of about 50 mgto about 200 mg per administration, then followed by repeated doses ofabout 200 mg to about 1 g per administration. Depending on the needs ofthe patient, administration can be by slow infusion with a duration ofmore than one hour, by rapid infusion of one hour or less, or by asingle bolus injection.

Toxicity and therapeutic efficacy of the ApoA-I Mimics may be determinedusing standard pharmaceutical procedures in cell culture or experimentalanimals for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀. Inone embodiment, the ApoA-I Mimics exhibit large therapeutic indices.

VI. Assay Methods

The ApoA-I Mimics can be assayed for their ability to form α-helices inthe presence of lipids, to bind lipids, to form complexes with lipids,to activate LCAT, to promote cholesterol efflux, etc.

Methods and assays for analyzing the structure and/or function of theApoA-I Mimics are well-known in the art. Several methods are providedbelow. For example, the circular dichroism (CD) and nuclear magneticresonance (NMR) assays described in the examples below can be used toanalyze the structure of the ApoA-I Mimics, and particularly the degreeof helicity in the presence of lipids. The ability to bind lipids can bedetermined using the fluorescence spectroscopy assay described in theexamples below. The ability of the peptides and/or peptide analogues toactivate LCAT can be readily determined using the LCAT activationdescribed in the examples below The in vitro and in vivo assaysdescribed in the examples below can be used to evaluate the half-life,distribution, cholesterol efflux and effects on RCT.

Generally, ApoA-I Mimics according to the invention that exhibit theproperties listed in Table 10 below are considered to be particularlyuseful.

TABLE 10 Range 1 Range 2 % Helicity in the presence of lipids (R_(i) =30) >60% >80% (unblocked peptides having 22 amino acid residues) %Helicity in the presence of lipids (R_(i) = 30) >40% >60% (unblockedpeptides having 18 amino acid residues) % Helicity in the presence oflipids (R_(i) = 30) >60% >80% (blocked peptides having 18 or fewer aminoacid residues) Lipid binding (in the presence of small 0.5-10 μMunilamellar vesicles (“SUVs”)) peptide (R_(i) = 1-50) LCATactivation >38% >80% R_(i) is the lipid:peptide molar ratio.

The ability of an ApoA-I Mimic to form an α-helix in the presence oflipids can be demonstrated using the CD assay described below. Thosepeptides which are at least 40% helical (unblocked peptides containing18 or fewer amino acid residues) or 60% helical (blocked peptidescontaining 18 or fewer amino acid residues; unblocked peptidescontaining 22 or more amino acid residues) and that bind to lipids (at aconcentration of about 5 μM and a lipid:peptide molar ratio of about30), particularly those ApoA-I Mimics which contain a fluorescent Trp(W) or NaI residue, can be identified using the fluorescence assaydescribed below. However, for ApoA-I Mimics that do not containfluorescent residues, binding to lipids is observed when helicityincreases in the presence of lipids.

In one embodiment of the invention, the ApoA-I Mimics, particularlythose that exhibit lipid binding in the presence of SUVs (0.5-10 μMpeptide; lipid:peptide molar ratio in the range of 1 to 50), arescreened for their ability to activate LCAT, as peptides which activateLCAT are particularly useful in the methods described herein. In oneembodiment, ApoA-I Mimics exhibit at least about 38% LCAT activation ascompared with native human ApoA-I (as determined using the LCATactivation assay described herein). In another embodiment, the ApoA-IMimics exhibit 50%, 60%, 70%, 80% or even 90% LCAT activation ascompared with native human ApoA-I.

VII. Other Uses

The ApoA-I Mimics are useful in assays in vitro to measure serum HDL,e.g., for diagnostic purposes. Because the ApoA-I Mimics typicallyassociate with the HDL component of serum, the mimics may be used as“markers” for the HDL population. Accordingly, the present inventionalso relates to methods for measuring serum HDL concentration,comprising contacting serum HDL with an amount of ApoA-I Mimic thatassociates with the serum HDL and quantifying the amount ofApoA-1-associated HDL. Moreover, the ApoA-I Mimics may be used asmarkers for the subpopulation of HDL that is effective in reversecholesterol transport (“RCT”). To this end, the ApoA-I Mimic may beadded to or mixed with a mammalian serum sample comprising HDL; after anappropriate incubation time, the HDL component may be assayed bydetecting the incorporated ApoA-I Mimic. This may be accomplished usinglabeled ApoA-I Mimic (e.g., radiolabels, fluorescent labels, enzymelabels, dyes, etc.), or by immunoassays using antibodies (or antibodyfragments) specific for the ApoA-I Mimic.

Alternatively, labeled ApoA-I Mimics are useful in imaging procedures(e.g., CAT scans, MRI scans) to visualize the circulatory system, or tomonitor RCT, or to visualize accumulation of HDL at fatty streaks,atherosclerotic lesions, etc. (where the HDL should be active incholesterol efflux).

The invention further includes the following non-limiting, illustrativeexamples.

EXAMPLES Example 1 Synthesis of ApoA-I Mimics

The ApoA-I Mimics are prepared by solid phase peptide synthesis (SPPS)using Fmoc (9-fluorenylmethyloxycarbonyl) chemistry. The C-terminalresidue is covalently bound to a 4-methylbenzhydrylamine (MBHA) resin.The other amino acid residues are then incorporated by repetitiveremoval of the Fmoc protecting group and coupling of protected aminoacid. After solid phase assembling of the peptide, the peptide iscleaved from the resin with trifluoroacetic acid (TFA). The crudepeptide is recovered by precipitation and dried. The identity of thecrude peptide is confirmed by MS analysis and amino acid analysis.

Example 2 Purification of ApoA-I Mimics

Purification of ApoA-I Mimics prepared according to Example 1 isperformed by preparative reverse phase HPLC with a C18 stationary phase(grafted silica, 15 μm particle size, 120 Å pore size) using awater/acetonitrile gradient (with 0.1% TFA counter ion). The elutingfractions are detected by UV absorbance at 220 nm. Each run processesapproximately 15 g of crude peptide, with pure fractions being pooledand concentrated on a rotary evaporator. The peptide solution is furtherpurified using the C18 HPLC column used in the first purification step.The peptide solution is then concentrated on a rotary evaporator toremove acetonitrile and freeze-dried.

Next, the lyophilized peptide powder is re-solubilized in 90% water/10%acetonitrile and the counter ion is exchanged for acetate through ionexchange chromatography (Dowex resin, 90% water/10% acetonitrile elutionmedia). The purified peptide with acetate counter ion is filteredthrough a sterile 0.22 micrometer membrane and freeze dried.

Example 3 Synthesis of Peptide 16 (SEQ ID NO: 16)

Peptide 16 (SEQ ID NO: 16) was synthesized on a solid phase supportusing Fmoc (9-fluorenylmethyloxycarbonyl) chemistry. The C-terminalisonipecotinyl residue was covalently bound to resin via a Wang typelinker. Protecting groups used for the amino acids were: t-Butyl groupfor Glu and Asp, Boc group for Lys, Pbf group for Arg, Trt group for Asnand Gln.

The solid phase assembling of the peptide was performed manually in a601 reactor equipped with a fitted disk, a mechanical stifling andnitrogen bubbling. The resin, p-methyl-benzhydrylamine resin(polystyrene-1%-divinylbenzene), was swelled and washed withdichloromethane (DCM)/dimethylformamide (DMF) (95/5). Incorporation ofthe C-terminal residue was achieved by coupling of the C-terminalisonipecotic acid esterified on a MPPA linker (Wang type linker). Thecoupling reaction was carried out with 1.35 eq of Fmoc-Inp-MPPA-linker,1.35 eq. of N-hydroxybenzotriazole (HOBt),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP) and 4.05 eq. of diisopropylethylamine (DIEA) in DMF/DCM (50/50).After coupling, the resin was washed 3 times with DMF.

The peptide chain was assembled on the resin by repetitive removal ofthe Fmoc protecting group and coupling of protected amino acid. Allamino acids were coupled following the same cycle: First, the Fmocprotecting group was removed in piperidine (35% in DMF) by threerepeated cycles. (The Fmoc deprotection reaction took about 16 min.)After the removal of the Fmoc protecting group, the resin was washedwith DMF in nine repeated cycles. The Fmoc protected amino acid residues(2 eq) were then coupled with 2 equivalents ofN,N′-diisopropylcarbodiimide (DIC)/HOBt in a mixture of DMF and DCM(50/50). (The coupling step took about one hour to overnight.) Theninhydrin test was used to determine whether the coupling reaction wascomplete. If the ninhydrin test indicated that the coupling reaction wasincomplete, the coupling was repeated with a lower excess (0.5-1 eq) ofamino acid, PYBOP, HOBt in DMF/DCM and DIEA. After the coupling step,the resin was washed with DMF in three repeated cycles.

The peptide was then cleaved from the resin and deprotected. Cleavagefrom the resin and deprotection were performed by batches in a mixtureof TFA/water/anisole (90/5/5 v/v/v) at a concentration of 5 ml/g ofpeptide to resin for 2.5 hours at room temperature. During progressiveaddition of the resin to the reagent mixture, temperature was regulatedto stay below 25° C. The peptide was soluble in TFA and was extractedfrom the resin by filtration through a fitted disc. After concentrationon a rotary evaporator, the peptide was precipitated in coldmethyl-t-butyl ether (MTBE) (0° C.±5° C.) and filtered. The crudepeptide was washed with MTBE and dried under reduced pressure in an ovenat 30° C.

After removal of the last Fmoc protecting group, the peptide was treatedwith TFA/H₂O for cleavage and removal of the side chain protectinggroups. Crude peptide was then precipitated from cold ether andcollected by filtration.

Example 4 Purification of Peptide 16 (SEQ ID NO: 16)

Peptide 16 (SEQ ID NO: 16) prepared according to Example 3 was purifiedby preparative reverse phase HPLC (high pressure liquid chromatography)with a C18 stationary phase using a water/acetonitrile gradient (withTFA counter ion). A Prochrom LC110 column was packed with a new ordedicated stationary C18 phase (grafted silica, 15 micron particle size,120 Angström pore size). Packing of the column was controlled by a SSTfor the number of plates and the tailing factor.

On a Prochrom LC 110 column, the amount of peptide injected for each runwas around 15 g of crude peptide dissolved in water/acetonitrile (80/20)at a concentration of approximately 75 g/L. The column was run with agradient of buffer B in buffer A (flow rate approximately 450 mL/min andUV detection at 220 nm): buffer A=0.1% TFA in water; bufferB=acetonitrile/0.1% TFA in water (80/20), under the followingconditions:

Column: Symmetry C18, 5 μm, 250 × 4.6 mm, 100 Å Gradient: 40% buffer Bto 55% buffer B in 30 minutes at 1 mL/min Temperature: 60° C. Detector:210 nm

Eluting fractions were analyzed by analytical HPLC and pooled in fourcategories: Waste, Front Impure, Pure, and Back Impure, according topreset specifications. The in-process HPLC purity specifications forclassifying the fractions into pools are:

Waste:  <80% Pure: ≧95% Front and Back Impure: ≧80% to <95%

To assure a better recovery yield of the product, the impure fractionsclose to the pure ones (front impure and back impure) were subjected toa recyling run on the same column. The “pure pools” were concentrated ona rotary evaporator to remove acetonitrile.

Example 5 Counter-Ion Exchange and Drying of Peptide 16 (SEQ ID NO: 16)

The pure pools from Example 4 were mixed and stirred for homogenisation.Concentration of pure Peptide 16 (SEQ ID NO: 16) was performed usingreverse phase HPLC on the preparative column that served forpurification. On a Prochrom LC 110 column, the volume of pure peptideinjected for each run was around 20 L at a concentration ofapproximately 5 g/L. The column was run with a steep gradient of bufferB in buffer A (flow rate approximately 450 ml/min and UV detection at220 nm): buffer A=0.1% TFA in water; buffer B=acetonitrile/0.1% TFA inwater (80/20).

The solvent volume for the whole peak was collected, concentrated on arotary evaporator to remove acetonitrile and freeze dried on a bottlefreeze dryer. The resultant freeze-dried pools of purified peptide weremixed in water/acetonitrile (90/10) at a concentration of 80 g/L andstirred to dissolve completely before ion exchange chromatography onDowex acetate, strongly basic, 50-100 mesh resin. (Dowex acetate wasobtained by treating Dowex Cl resin with 1N NaOH, then rinsing withpurified water, treatment with AcOH/H₂O (25/75), and rinsing withpurified water.) The sample was eluted with water/acetonitrile (90/10).The solvent volume for the whole peak was collected, and concentrated ona rotary evaporator if the elution volume was too large. The purifiedpeptide solution was filtered through a sterile filtration capsule (0.22micrometer), and lyophilized on a shelf freeze dryer.

Example 6 Purity Analysis of Peptide 16 (SEQ ID NO: 16)

The purity of Peptide 16 (SEQ ID NO: 16) was determined using analyticalreverse phase HPLC analysis. Purity was established by integration ofthe areas of all peaks (area normalization). The analysis was performedusing a Waters Alliance HPLC system with: a module 2695 composed of adual piston pump, a degasser, an automatic injection system, a Peltierregulated column oven; a UV detector module 2487; and Empower ProVersion 5.00 software. The column used was a Symmetry C18 (5μ) orequivalent, 250×4.6 mm column. The column temperature was 60° C.Injections were eluted on a gradient profile at a flow rate of 1 mL/min.Eluent A is 0.1% TFA (e.g. Acros 13972) in milli-Q water, while eluent Bis 0.1% TFA in acetonitrile HPLC gradient grade (e.g. SDS 00637G). Thegradient profile is shown below:

Time (min) Eluent A (%) Eluent B (%) 0.0 57 43 30.0 50 50 45.0 20 8046.0 0 100 51.0 0 100 52.0 57 43

Peptide 16 (SEQ ID NO: 16) was detected by UV absorbance at 210 nm. Therun time was 45 min, with a delay of 22 min between injections forcolumn wash out. Peptide 16 (SEQ ID NO: 16) was weighed out in an HPLCvial and dissolved in purified water to provide a concentration ofapproximately 1.2 mg/mL. Peptide solutions were injected at 20 μL.

Example 7 Characterization of ApoA-I Mimics by LC-MS

A standard commercially available triple stage quadrupole massspectrometer (model TSQ 700; Finnigan MAT, San Jose Calif., USA) is usedfor mass determination. A pneumatically assisted electrospray (ESI)interface is used for sample introduction to the atmospheric pressureionization source of the mass spectrometer. The interface sprayer isoperated at a positive potential of 4.5 kV. The temperature of the steelcapillary is held at 200° C., whereas the manifold is at 70° C. Positiveions generated by this ion evaporation process enter the analyzer of themass spectrometer. The multiplier is adjusted to 1000 V. The analyzercompartment of the mass spectrometer is at 4E-6. All acquisitions areperformed at resolution <1μ.

ApoA-I Mimics are analyzed by direct infusion of the purified ApoA-IMimics using an ABI (Applied Biosystems) microbore system consisting ofa syringe pump (model 140B), an UV detector (model 785A) and anoven/injector (model 112A). The solvent system consists of water(solvent A) and acetonitrile (solvent B), each containing 0.1% TFA.ApoA-I Mimics are infused using either a gradient or isocraticconditions and are eluted from an Aquapore C18 column. The flow rate istypically 300 μL/min. Concentration of each ApoA-I Mimic is about 0.03mg/mL, 20 μL of which is injected (e.g., 30 μmol).

Full scan MS experiments are obtained by scanning quadrupole 1 from m/z500-1500 in 4 s. Data are acquired using an Alpha DEC station and areprocessed using the software package provided by Finnigan MAT(BIOWORKS).

Example 8 Characterization of Peptide 16 (SEQ ID NO: 16) by LC-MS

The mass spectral analysis was carried out using a Thermo-Finnigan LCQAdvantage instrument. The source was Electrospray Ionisation (ESI-MS).Parameters MS: Nitrogen Gas Flow=30 arbitrary Units, Spray Voltage=5.2V,Capillary temperature=270° C., Capillary voltage=38V, Tube LensOffset=55V. A test solution of 100 μg/mL solution of Peptide 16 (SEQ IDNO: 16) in methanol/water/formic acid 47/47/6 v/v/v was analyzed (directinfusion into the MS at a flow rate of 5 μL/min injection with a 500 μLsyringe). The result obtained after deconvolution was in agreement withthe theoretical value.

Example 9 Amino Acid Analysis of ApoA-I Mimics

Amino acid analysis is performed using an ABI (Applied Biosystems) 420Amino Acid Analyzer. This system consists of three modules: a hydrolysisand derivatisation instrument, a reverse-phase HPLC and a data system.Peptide samples are applied (3 times in triplicate) on porous glassslides and subsequently hydrolyzed under gas phase conditions (155° C.,90 min.). After removal of the HCl, the resulting amino acids areconverted to PTC-AA (Phenylthiocarbamoyl-amino acids) using PITC(Phenylisothiocyanate). After transfer to the HPC sample loop theresulting mixtures are fractionated on an Aquapore C18 column using thegradient mode (Solvent A: 50 mmol ammonium acetate (NH₄Ac), pH 5.4, inwater; Solvent B: 32 mmol of sodium acetate (NaOAc) in aqueousacetonitrile) under conditions of temperature control. The HPLC data areprocessed by the software package provided by Applied Biosystems.Quantification is performed relative to a peptide standard delivered byApplied Biosystems.

Example 10 Amino Acid Analysis of Peptide 16 (SEQ ID NO: 16)

Peptide 16 (SEQ ID NO: 16) (about 700 μg) was hydrolyzed by 100 [t.L 6NHCl (e.g. Pierce 24308) at 110° C. for 20 hours into the constitutiveamino acids which, after derivatization, were separated and quantifiedagainst a standard mixture of amino acids (amino acid Standard H e.g.Pierce 20088). The amino acids were derivatized using o-phtalaldehyde(OPA-reagent e.g. Fluka 5061-3335) and 9-fluorenylmethylchloroformate(Fmoc-reagent e.g. Fluka 5061-3337), then injected on a C-18HPLC-column. An Agilent 1100 HPLC with UV detector and ChemstationSoftware was used for the analysis. The column used was a Hypersil ODScolumn 200×2.1 mm, 5 μm. The gradient used was 0-60% B in 17 min up to100% B for 7 min at a flow rate of 0.45 mL/min. Buffer A=2.3 g sodiumacetate in 1000 mL H₂O+180 μL triethylamine, pH adjusted to 7.2 with 2%acetic acid solution +3.3 ml tetrahydrofuran. Buffer B=2.3 g sodiumacetate in 200 ml H₂O, pH adjusted to 7.2 with 2% acetic acid solution+400 mL acetonitrile+400 mL methanol. Amino acid measurements wereperformed in triplicate, with amino acids detected by UV absorbance at368 and 262 nm. Pierce standard solution was injected both before andafter the triplicate injection of the peptide sample.

Example 11 Preparation of Peptide/Lipid Complexes by Co-Lyophilization

50 mg of an ApoA-I Mimic is dissolved in 1 mL of glacial acetic acid ina 1 mL clear glass vial with cap. Dissolution of the peptide is aided byoccasional vortexing over a period of 10 minutes at room temperature. 50mg of dipalmitoyl phosphatidylcholine (DPPC; Avanti Polar Lipids, 99%Purity, product #850355) and 50 mg of egg sphingomyelin (NOF) aredissolved in 1 mL of glacial acetic acid. DPPG is dissolved in 90%glacial acetic acid 10% water mixture (v/v) at a concentration of 10mg/mL. DPPG dissolution is aided by incubation at 37° C. ApoA-I Mimic,sphingomyelin, DPPC and DPPG solutions are mixed to obtain weight ratioof ApoA-I Mimic:sphingomyelin:DPPC:DPPG of 1:1.35:1.35:0.30,respectively. The resulting solution is frozen at −20° C. andlyophilized for over 12 h.

The lyophilized powder is hydrated in bicarbonate saline buffer (20 mMsodium bicarbonate, 130 mM NaCl, pH 8.2) to obtain 10 mg/mL finalconcentration of ApoA-I Mimic. The mixture is agitated to facilitaterehydration. Following hydration the pH is adjusted with 1N NaOHsolution to pH 7.4. To aid complex formation hydrated powder isincubated in a water bath at 50° C. for 15 minutes following by keepingit at room temperature for 15 min. The heating and cooling is repeateduntil clear to translucent solution of ApoA-I Mimic/phospholipidcomplexes in buffer is obtained.

Example 12 Preparation of a Peptide 16 (SEQ ID NO: 16)/lipid complex byhomogenization

A sodium phosphate buffer (12 mM, pH 8.2) was prepared and heated to 50°C.

A DPPG dispersion was prepared by dispersing DPPG in buffer at aconcentration of 45 mg/mL. A peptide solution was prepared by dissolvingPeptide 16 (SEQ ID NO: 16) in buffer at a concentration of 30 mg/ml. ThepH of the peptide solution was adjusted to about 8.2 by addition ofNaOH. The peptide solution was then combined with the DPPG dispersionand incubated at 50° C. until a clear solution was observed, forming apeptide/DPPG solution.

A sphingomyelin/DPPC dispersion was prepared by dispersing sphingomyelinand DPPC in buffer at a concentration of 38.3 mg/mL of each ofsphingomyelin and DPPC. The sphingomyelin/DPPC dispersion was then mixedusing high shear mixing.

The peptide/DPPG solution and the sphingomyelin/DPPC solution werecombined and homogenized using a high pressure homogenizer (Avestin C3)until the solution became translucent and complexes formed. Followinghomogenization, an isotonicity agent was added (130 mM NaCl). Thesolution was then sterile filtered and filled into glass vials. Thefinal concentration of Peptide 16 (SEQ ID NO: 16) in the solution was 15mg/mL.

Example 13 Analysis of a Peptide 16 (SEQ ID NO: 16)/Lipid Complex

a. Size Distribution of the Complex

The identity of the Peptide 16 (SEQ ID NO: 16)/lipid complex preparedaccording to Example 12 was verified and the size distribution of thecomplexes was determined using Gel Permeation Chromatography (GPC). ATosoh TSK-GEL G3000SW_(XL) (7.8 mm ID, 30 cm length) was used for theseparation. Injections were eluted using a 6 mM phosphate buffercontaining 150 mM NaCl (pH 7.4) and an isocratic flow rate of 1 ml/min.Samples were prepared by 20× dilution with mobile phase and an injectionvolume of 100 μL was used. Column performance was checked before eachrun by injection of four molecular weight standards. The complex wasdetected by UV at 220 nm wavelength. Identity of the complex wasconfirmed by comparison of the retention time of the complex to thereference standard. Size distribution of the complex was reported as thepercentage of total peak area in the chromatogram. A representative GPCchromatogram for the Peptide 16 (SEQ ID NO: 16)/lipid complex preparedaccording to Example 12 is shown in FIG. 5.

b. Identity, Purity, and Content of Peptide 16 (SEQ ID NO: 16) of theComplex

The identity, purity and content of Peptide 16 (SEQ ID NO: 16) of thecomplex was determined using Ultra Performance Liquid Chromatography(“UPLC”) with UV detection at 215 nm wavelength. An Acquity BEH C18 100mm column with I.D. of 2.1 mm and particle size of 1.7 μm was used forthis separation. Injections were eluted using a binary gradient mobilephase of 0.1% (v/v) TFA in methanol/acetonitrile/water at 52.5/22.5/22(v/v/v) ratio and 0.1% (v/v) TFA in methanol/acetonitrile/water at56/24/20 (v/v/v) ratio. Samples were prepared by 20× dilution andinjected using a 7.5 μL injection volume. The combination ofmobile-phase organic solvents dissolved the complexes and separatedPeptide 16 (SEQ ID NO: 16) from the lipids of the complex. The identityof Peptide 16 (SEQ ID NO: 16) was confirmed by comparison of itsretention time to the reference standard. Purity of Peptide 16 (SEQ IDNO: 16) was reported as the percentage of total peak area in thechromatogram. Content of Peptide 16 (SEQ ID NO: 16) was calculated usinga calibration curve constructed from diluted solutions of Peptide 16(SEQ ID NO: 16) reference standard.

c. Determination of Lipid Content in the Complex

The lipid content of the Peptide 16 (SEQ ID NO: 16)/lipid complexprepared according to Example 12 was determined using an enzymatic assayutilizing the DAOS method. The assay kit was manufactured by Wako PureChemical Industries, Ltd (Phospholipids C kit). Samples were diluted 75×using phosphate buffer. The enzymes in the assay kit hydrolyzedsphingomyelin and DPPC to release choline, which then reacted withseveral other enzymes to activate a blue pigment. The blue pigment wasdetected spectraphotometrically. Samples were quantified from acalibration curve made from dilutions of sodium cholate and the bluepigment. The hydrolyzed sphingomyelin and DPPC both contained cholineand are thus quantified by this method.

Example 14 Superose 6 Gel Filtration Chromatography of Human HDL

Human HDL₂ is prepared as follows: 300 mL frozen human plasma (MannheimBlutspendzentrale #1185190) is thawed, adjusted to density 1.25 usingsolid potassium bromide, and centrifuged for 45 hours at 40,000 PRMusing a Ti45 rotor (Beckman) at 20° C. The resultant floating layer iscollected, dialyzed against distilled water, adjusted to density 1.07with solid potassium bromide, and centrifuged as described above for 70hours. The bottom layer (at a level of 1 cm above the tube bottom) iscollected, 0.01% sodium azide is added, and the layer is stored at 4° C.for 4 days. 20 μL, of the HDL₂ is loaded onto a Pharmacia Superose 6FPLC gel filtration chromatography system using 0.9% NaCl as columneluate. The column flow rate is 0.5 mL/min. The column eluate ismonitored by absorbance or scattering of light of wavelength 254 nm. Aseries of proteins of known molecular weight and Stokes' diameter areused as standards to calibrate the column for the calculation of Stokes'diameters of the particles (Pharmacia Gel Filtration Calibration KitInstruction Manual, Pharmacia Laboratory Separation, Piscataway, N.J.,revised April 1985).

Example 15 Determination of Peptide 16 (SEQ ID NO: 16) in Rat and MonkeyPlasma Using Protein Precipitation with Liquid Chromatography and TandemMass Spectrometric Detection (LC-MS/MS)

Concentrations of Peptide 16 (SEQ ID NO: 16) were determined in rat ormonkey plasma over the concentration range 1 to 500 μg/mL range usingblank matrix. Isotopically labeled Peptide 16 (SEQ ID NO: 16) was usedas an internal standard solution and added to thawed plasma samples. Thesamples were then subjected to protein precipitation usingwater:acetonitrile:TFA (70:20:10 v/v/v), followed by mixing andcentrifugation. The supernatant was transferred to a clean 96 well plateand water:acetonitrile:TFA (70:30:0.1 v/v/v) was added to each wellfollowed by mixing and centrifugation before LC-MS/MS analysis. The LCconditions were: Acquity UPLC and Turbo IonSpray (positive ion) (MS/MS),using a BEH Shield RP18 column running a gradient ofwater:acetonitrile:TFA 0.1%.

Concentrations of Peptide 16 (SEQ ID NO: 16) in calibration standardsand QC samples were determined using least squares linear regressionwith the reciprocal of the concentration (1/x) as weighting.

Example 16 Measurement of Pharmacokinetics of a Peptide 16 (SEQ ID NO:16)/Lipid Complex in Rats

Pharmacokinetics of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)were evaluated in Windstar rats.

Nine animals per sex per group were included for the evaluation ofpharmacokinetics. Animals in the vehicle control group received 130 mMsodium chloride in 12 mM phosphate buffer, pH 8.2, intravenously at 20mL/Kg. Animals in the Peptide 16 (SEQ ID NO: 16)/lipid complex treatmentgroups received 15, 30 or 60 mg/kg administered every other day byintravenous infusion. Approximately 0.5 mL of blood was drawn from theretro-orbital sinus under isoflorane anesthesia and collected in tubescontaining Na₃EDTA as an anticoagulant from cohorts of 3 animals pergroup at baseline and 0.0833, 0.5, 1, 2, 6, 12, 24 and 48 hourspost-dose on Day 0 and Day 26. Thus, each cohort of animals had blooddrawn at three different timepoints. Plasma was separated followingcentrifugation and stored frozen at −20° C. until analysis. Peptidelevels were analyzed by LC-MS/MS as described in Example 8.Pharmacokinetics parameters were determined from individual plasmaconcentrations by non-compartmental analysis using Kinetica 4.4.1. Theplasma levels of Peptide 16 (SEQ ID NO: 16) increased rapidly post-dose,then were quantifiable up to 6 hr following the end of infusion inanimals that were administered the Peptide 16 (SEQ ID NO: 16)/lipidcomplex at 15 and 30 mg/kg doses. Detectable levels of Peptide 16 (SEQID NO: 16) were observed up to 12 hrs in animals treated with 60 mg/kgin both sexes. As expected for an intravenously administered drug, theT_(max) was immediate post dose. The estimated half-life of circulatinglevels of Peptide 16 (SEQ ID NO: 16) was between 0.5 and 5 hours in ratsof both sexes, and it appeared to increase in a dose-dependent manner.The clearance and volume of distribution decreased with increasing dose.Based on the volume of distribution it could be inferred that thePeptide 16 (SEQ ID NO: 16)/lipid complex was generally distributed inplasma.

Example 17 Measurement of Pharmacokinetics of a Peptide 16 (SEQ ID NO:16)/Lipid Complex in Monkeys

Pharmacokinetics of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)were evaluated in Cygomolus monkeys.

Animals in the vehicle control group received 130 mM sodium chloride in12 mM phosphate buffer, pH 8.2, intravenously at 10 mL/Kg. Animals inthe Peptide 16 (SEQ ID NO: 16)/lipid complex treatment groups received15, 30 or 60 mg/kg administered every other day by intravenous infusion.Blood was collected into tubes containing Na₃EDTA as an anticoagulant,at baseline, at the end of infusion, and then at 1, 2, 6, 12, 24 and 48hours post-dose. At each time point, approximately 1 mL of blood wasdrawn from the femoral vessel, while the animal was held restrainedwithout any anesthesia. Plasma was separated following centrifugationand stored frozen at −20° C. until analysis. Peptide 16 (SEQ ID NO: 16)levels were analyzed by LC-MS/MS as described in Example 8.Pharmacokinetics parameters were determined from individual plasmaconcentrations by non-compartmental analysis using Kinetica 4.4.1.Peptide 16 (SEQ ID NO: 16) was detected in plasma for up to 12 hrfollowing the end of infusion in animals administered with the Peptide16 (SEQ ID NO: 16)/lipid complex at 15 mg/kg in both sexes. Detectablelevels of Peptide 16 (SEQ ID NO: 16) were observed up to 24 hrs inanimals treated with 30 and 60 mg/kg. The phospholipid levels alsoincreased post dose, then returned to baseline levels over a similartimeframe to that of Peptide 16 (SEQ ID NO: 16). As expected for anintravenously administered drug, the T_(max) was immediate post dose.The estimated half-life of circulating levels of Peptide 16 (SEQ ID NO:16) was between 2 and 7 hours in monkeys of both sexes, and it appearedto increase in a dose-dependent manner. The clearance and volume ofdistribution decreased with increasing dose. Based on the volume ofdistribution it could be inferred that the Peptide 16 (SEQ ID NO:16)/lipid complex was distributed primarily in the plasma compartment.

Example 18 Cholesterol Mobilization in Rabbits

a. Preparation of the Peptide 16 (SEQ ID NO: 16)/Lipid Complex

Peptide 16 (SEQ ID NO: 16) was synthesized by F-moc synthesis accordingto Example 3 and purified by a reverse phase chromatography according toExample 4.

Peptide 16 (SEQ ID NO: 16) was then complexed with a mixture ofsphingomyelin, DPPG, and DPPC by co-lyophilization of solutions ofPeptide 16 (SEQ ID NO: 16), sphingomyelin, DPPG, and DPPC in a glacialacetic acid:water mixture. The resultant lyophilized powder wasreconstituted with buffer (sodium phosphate buffer, 12 mM, pH 8.2) toform a suspension of Peptide 16 (SEQ ID NO: 16)/lipid complex having aweight ratio of Peptide 16 (SEQ ID NO: 16):sphingomyelin:DPPC:DPPG of1:1.35:1.35:0.30.

b. Administration of the Peptide 16 (SEQ ID NO: 16)/Lipid Complex toRabbits

New Zealand male rabbits weighing between 3 to 4 kg were used todemonstrate cholesterol mobilization by the Peptide 16 (SEQ ID NO:16)/lipid complex.

The animal room conditions were as follows: temperature, 22±2° C.;relative humidity, 55±15%; and a 12 hour light/12 hour dark cycle.

Animals were acclimatized for at least 7 days before the beginning ofthe study. The animals received ad libitum a controlled pellet diet on adaily basis. Water was available ad libitum throughout the study.

Before administration of the Peptide 16 (SEQ ID NO: 16)/lipid complex,the animals were fasted overnight. The animals were weighed just beforeadministration of the Peptide 16 (SEQ ID NO: 16)/lipid complex. ThePeptide 16 (SEQ ID NO: 16)/lipid complex was administered intravenouslyat a dosage rate of 20 mg/kg. The volume administered was based onweight. Feeding was resumed approximately 6 hours after theadministration of the Peptide 16 (SEQ ID NO: 16)/lipid complex.

c. Analysis of Blood Samples

Prior to the collection of blood samples, the animals were fastedovernight. Blood was collected at baseline, then 5 min, 15 min, 30 min,1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 30 hr and 34 hr after initiating theinfusion. Blood samples were withdrawn from the jugular vein or from themarginal vein of the ear. Blood was withdrawn from the jugular veinusing a syringe mounted with a needle with EDTA (approximately 1 mL ofblood per sampling time). Immediately after collection, blood sampleswere kept at approximately 4° C. to avoid alteration of the bloodsample. Blood specimens were centrifuged (3500 g for 10 minutes atapproximately 5° C.). Plasma specimens were separated and aliquoted (3aliquots of at least 200 μL (aliquots A, B, C)) and stored atapproximately −80° C. The remaining blood clot was discarded.

Serum phospholipid (Phospholipid B, Kit #990-54009, Wako Chemicals GmbH,Neuss, Germany), triglycerides (Triglycerides, Kit #1488872, BoehringerMannheim Corporation, Indianapolis, Ind.), total cholesterol andunesterified cholesterol were determined using commercially availablekits for a Hitachi 912 Automatic Analyzer (Roche DiagnosticsCorporation, Indianapolis, Ind.).

Lipoprotein profiles were analyzed using gel filtration chromatographyon a Superose 6HR 1×30 cm column equipped with on-line detection fortotal or free cholesterol as described by Kieft et al. (J Lipid Res1991; 32:859-866, 1991). The area under the peaks corresponding tolipoproteins with the sizes of VLDL, LDL and HDL were integrated. Thefraction of the free or total cholesterol of each peak was multiplied bythe total plasma cholesterol or free cholesterol determined by anautomatic analyzer to determine VLDL, LDL and HDL free and totalcholesterol. Esterified cholesterol in serum and in the lipoproteinfractions VLDL, LDL and HDL was calculated by subtracting freecholesterol from total cholesterol values.

The increase in HDL fraction of total cholesterol following infusion ofcomplexes was plotted as a function of time and is illustrated in FIG.6. The rabbits' total HDL cholesterol increased upon administration ofthe Peptide 16 (SEQ ID NO: 16)/lipid complex, indicating tissuecholesterol mobilization and transfer to HDL.

Example 19 Cholesterol Mobilization in Rabbits

a. Preparation of the Peptide 16 (SEQ ID NO: 16)/Lipid Complex

The Peptide 16 (SEQ ID NO: 16)/lipid complex was prepared according toExample 12. The Peptide 16 (SEQ ID NO: 16)/lipid complex had a weightratio of Peptide 16 (SEQ ID NO: 16):sphingomyelin:DPPC:DPPG of1:1.2125:1.2125:0.075 and a weight ratio of peptide:lipid of 1:2.5.

b. Administration of the Peptide 16 (SEQ ID NO: 16)/Lipid Complex toRabbits

New Zealand male rabbits weighing between 3 to 4 kg were used to show anincrease in HDL levels in rabbits by the Peptide 16 (SEQ ID NO:16)/lipid complex.

The animal room conditions were as follows: temperature, 22±2° C.;relative humidity, 55±15%; and a 12 hour light/12 hour dark cycle.

Animals were acclimatized for at least 7 days before the beginning ofthe study. The animals received ad libitum a controlled pellet diet on adaily basis. Water was available ad libitum throughout the study.

Before administration of the Peptide 16 (SEQ ID NO: 16)/lipid complex,the animals were fasted overnight. The animals were weighed just beforeadministration of the Peptide 16 (SEQ ID NO: 16)/lipid complex. Toinvestigate the minimal dose at which cholesterol mobilization could bedetected, the animals were dosed with 2.5, 5 and 10 mg/kg of the Peptide16 (SEQ ID NO: 16)/lipid complex or a phosphate buffered saline control.Four animals were studied per dose group. Feeding was resumedapproximately 6 hours after the administration of the Peptide 16 (SEQ IDNO: 16)/lipid complex or phosphate buffered saline control.

c. Analysis of Blood Samples

Prior to the collection of blood samples, the animals were fastedovernight. Blood was collected at baseline, then 5 min, 15 min, 30 min,1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 30 hr and 34 hr after initiating theinfusion. Blood samples were withdrawn from the jugular vein or from themarginal vein of the ear. Blood was withdrawn from the jugular veinusing a syringe mounted with a needle with EDTA (approximately 1 mL ofblood per sampling time). Immediately after collection, blood sampleswere kept at approximately 4° C. to avoid alteration of the bloodsample. Blood specimens were centrifuged (3500 g for 10 minutes atapproximately 5° C.). Plasma specimens were separated and aliquoted (3aliquots of at least 200 μL (aliquots A, B, C)) and stored atapproximately −80° C. The remaining blood clot was discarded.

Serum phospholipid (Phospholipid B, Kit #990-54009, Wako Chemicals GmbH,Neuss, Germany), triglycerides (Triglycerides, Kit #1488872, BoehringerMannheim Corporation, Indianapolis, Ind.), total cholesterol andunesterified cholesterol were determined with commercially availablekits for a Hitachi 912 Automatic Analyzer (Roche DiagnosticsCorporation, Indianapolis, Ind.).

Lipoprotein profiles were analyzed using gel filtration chromatographyon a Superose 6HR 1×30 cm column equipped with on-line detection fortotal or free cholesterol as described by Kieft et al. (J Lipid Res1991; 32:859-866, 1991). The area under the peaks corresponding tolipoproteins with the sizes of VLDL, LDL and HDL were integrated. Thefraction of the free or total cholesterol of each peak was multiplied bythe total plasma cholesterol or free cholesterol determined by anautomatic analyzer to determine VLDL, LDL and HDL free and totalcholesterol. Esterified cholesterol in serum and in the lipoproteinfractions VLDL, LDL and HDL was calculated by subtracting freecholesterol from total cholesterol values.

The increase in HDL fraction of free cholesterol following infusion ofcomplexes was plotted as a function of time and is illustrated in FIG.7. A clear increase in HDL free cholesterol over baseline was apparentat a dose of 2.5 mg/kg, indicating high potency of the Peptide 16 (SEQID NO: 16)/lipid complex. At five and 20 minutes after starting theinfusion, the cholesterol was increased 30% above baseline. Theseincreases were statistically significant (p<0.05 by a paired two tailedstudent T test). In contrast, there was no change from baseline in theplacebo treatment group.

The pharmacological effect of the Peptide 16 (SEQ ID NO: 16)/lipidcomplex at a 2.5 mg/kg dose was further evident by comparing theoriginal scans of the lipoprotein fractions eluting from the HPLC sizeexclusion column, which are illustrated in FIG. 8. There is a clearincrease relative baseline in the HDL free cholesterol fraction of theHPLC chromatograms following injection.

Example 20 Dose Response of a Peptide 16 (SEQ ID NO: 16)/Lipid Complex

Dose response of a Peptide 16 (SEQ ID NO: 16)/lipid complex (the lipidsbeing sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)was evaluated in New Zealand white rabbits.

In a fasted New Zealand White rabbit cholesterol mobilization model, thePeptide 16 (SEQ ID NO: 16)/lipid complex at concentrations of 5, 10, or15 mg/mL (based upon the peptide concentration) or a phosphate bufferedsaline vehicle control were administered, intravenously, at a rate of 1mL/min to fasted animals at an infusion volume of 2 mL/kg. There werethree animals per dose group. The final doses were 0, 10, 20 or 30mg/kg. Blood was collected at baseline, then 5 min, 15 min, 30 min, 1hr, 2 hr, 4 hr, 6 hr, 8 hr, 30 hr and 34 hr after initiating theinfusion. Plasma lipid and lipoprotein levels were then determined.Lipoprotein levels were determined by HPLC size exclusion fractionationwith inline free and total cholesterol detection according to a methoddescribed by Usui, S., Hara, Y., Hosaki, S., and Okazaki, M., A newon-line dual enzymatic method for simultaneous quantification ofcholesterol and triglycerides in lipoproteins by HPLC. J. Lipid Res. 43,805-814 (2002). The area under the main peaks corresponding tolipoproteins with the sizes of VLDL, LDL and HDL were integrated. Thefraction of the free or total cholesterol in each peak was multiplied bythe total plasma cholesterol or free cholesterol to determine the levelof cholesterol in each fraction. Cholesterol ester levels in eachfraction were determined by subtracting the free cholesterol from thetotal cholesterol in each fraction. In this model, increases in plasmaor HDL cholesterol levels are indicative of tissue cholesterolmobilization and transfer to HDL.

FIG. 9 shows the dose dependent increase plasma phospholipids followinginfusion of the Peptide 16 (SEQ ID NO: 16)/lipid complex into rabbits.This increase reflects the circulating levels of the Peptide 16 (SEQ IDNO: 16)/lipid complex, since phopholipid is a component of the Peptide16 (SEQ ID NO: 16)/lipid complex. Peptide 16 (SEQ ID NO: 16) levelspeaked within the first 30 minutes then decreased towards baselinelevels. A dose dependent increase in cholesterol mobilization was alsoobserved. This was evident by the increase in both the total plasmacholesterol (FIG. 10A) and total HDL cholesterol levels (FIG. 11A). Themajority of the cholesterol increase was in the form of free cholesterol(FIGS. 10 and 11).

An increase in total and free cholesterol in the LDL fraction (FIGS. 11Cand 11D) was observed at the two highest doses. The increase in freecholesterol was about equal to that of the total cholesterol, indicatinglittle increase in cholesterol ester in this fraction. An increase infree cholesterol in the LDL fraction, in the absence of an increase incholesterol ester, indicates this increase does not represent anincrease in typical cholesterol ester rich LDL. The complexes appearingin this lipoprotein fraction are likely a product of the infused Peptide16 (SEQ ID NO: 16)/lipid complex that has gained cholesterol through thecholesterol mobilization process. Observed increases in VLDL cholesterolwere distributed between the esterified and unesterified cholesterolfractions. Triglyceride levels increased transiently over the first fourto six hours at all Peptide 16 (SEQ ID NO: 16)/lipid complex doses (FIG.12). There was no obvious relationship between the dose and triglycerideincrease.

Example 21 Minimal Effective Dose of a Peptide 16 (SEQ ID NO: 16)/LipidComplex

The minimal effective dose of a Peptide 16 (SEQ ID NO: 16)/lipid complex(the lipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)was evaluated in New Zealand white rabbits.

The minimal dose at which cholesterol mobilization could be detected wasinvestigated. Animals were dosed with 0, 2.5, 5 and 10 mg/kg of thePeptide 16 (SEQ ID NO: 16)/lipid complex. Four animals were studied perdose group. A pharmacological effect was most evident by the increase infree cholesterol in the HDL fraction compared to baseline levels (FIG.13). This was expected because the majority of the initial cholesterolincrease after infusion of the Peptide 16 (SEQ ID NO: 16)/lipid complexis free cholesterol in the HDL fraction. In addition, free cholesterolrepresents about one third of the total HDL cholesterol, making theincrease in this fraction easier to detect. A clear increase in HDL freecholesterol over baseline was apparent at a 2.5 mg/kg dose. At five and20 minutes after starting the infusion, the cholesterol was increased30% above baseline. These increases were statistically significant(p<0.05 by a paired two tailed student T-test). In contrast, there wasno change from baseline in the control group.

The pharmacological effect of the Peptide 16 (SEQ ID NO: 16)/lipidcomplex at a 2.5 mg/kg or 5 mg/kg dose was further evident by comparingthe original scans of the lipoprotein fractions eluting from the HPLCsize exclusion column. As can be seen in these two examples, in FIG. 14,there is a clear increase in free cholesterol relative baseline in theHDL fraction of the HPLC chromatograms. This is shown by the increase inthe area under the HDL peak for the sample collected at 20 minutes afterinitiating the infusion of the Peptide 16 (SEQ ID NO: 16)/lipid complex(light line in FIG. 14) compared to the area under the HDL peak atbaseline (dark line in FIG. 14).

Example 22 Effect of Infusion Rate on Efficacy of a Peptide 16 (SEQ IDNO: 16)/Lipid Complex

The effect of infusion rate on efficacy of a Peptide 16 (SEQ ID NO:16)/lipid complex (the lipids being sphingomyelin, DPPC, and DPPG in aweight ratio of 1:1.2125:1.2125:0.075, and the peptide:lipid weightratio being 1:2.5) was evaluated in New Zealand white rabbits.

The effect of the rate of infusion of the Peptide 16 (SEQ ID NO:16)/lipid complex on cholesterol mobilization was investigated. Peptide16 (SEQ ID NO: 16)/lipid complex at a concentration of 10 mg/mL (basedupon peptide concentration) or a phosphate buffered saline vehiclecontrol was infused at a dose volume of 2 mL/kg at a rate of either 1mL/min or 0.2 mL/min. The final dose of Peptide 16 (SEQ ID NO: 16)/lipidcomplex was 20 mg/kg. Four animals were studied in the Peptide 16 (SEQID NO: 16)/lipid complex groups and two animals in the vehicle controlgroups. The rabbits ranged in size from 2.2-2.8 kg.

The rate of increase in plasma phospholipid resulting from the infusionof the Peptide 16 (SEQ ID NO: 16)/lipid complex and rate of increase inplasma cholesterol resulting from the subsequent cholesterolmobilization was slower in the animals in which the Peptide 16 (SEQ IDNO: 16)/lipid complex was infused at a slower rate. However, the peakphospholipid and cholesterol mobilization levels were similar. FIG. 15shows that the increase in HDL free cholesterol following infusion ofthe Peptide 16 (SEQ ID NO: 16)/lipid complex at rate of 1 mL/min or 0.2mL/min was similar. Thus in this model, Peptide 16 (SEQ ID NO: 16)/lipidcomplex infusion rate, over the rates tested, had little or no effect oncholesterol mobilization.

Example 23 Pharmacokinetic Studies on a Peptide 16 (SEQ ID NO: 16)/LipidComplex in Rats and Monkeys

The pharmacokinetics of a Peptide 16 (SEQ ID NO: 16)/lipid complex (thelipids being sphingomyelin, DPPC, and DPPG in a weight ratio of1:1.2125:1.2125:0.075, and the peptide:lipid weight ratio being 1:2.5)was evaluated in rats and monkeys.

a. Assay Methodology

The concentrations of the Peptide 16 (SEQ ID NO: 16)/lipid complex inrat and monkey plasma were determined using a liquid chromatography withtandem mass spectrometry (LC-MS/MS) technique. Peptide 16 (SEQ ID NO:16), a component of the Peptide 16 (SEQ ID NO: 16)/lipid complex, wasextracted from plasma containing EDTA following precipitation of theprotein fraction by acetonitrile. The method measures the extractedPeptide 16 (SEQ ID NO: 16) and an internal standard of an isotopicallylabeled-Peptide 16 (SEQ ID NO: 16). The extracts were reconstituted andthe peptide assayed by ultra performance liquid chromatography combinedwith tandem mass spectrometers (MS/MS). The calibration range of themethod is 1-500 μg/mL with a sample volume of 25 μL. The peptideextraction and LC-MS/MS methods were validated in accordance withgeneral recommendations for bioanalytical method validation and incompliance with GLP (Good Laboratory Practice). The validation datashowed that the methods were sensitive, specific, accurate and preciseenough for the determination of Peptide 16 (SEQ ID NO: 16)/lipid complexin rat and monkey plasma.

b. Pharmacokinetic Studies in Rats

9 rats per sex per group were included for the evaluation oftoxicokinetics of the Peptide 16 (SEQ ID NO: 16)/Lipid complex followingdose administration on Day 0 (First dose) and Day 26. Animals in thevehicle control group received 130 mM sodium chloride in 12 mM phosphatebuffer, pH 8.2, intravenously at 20 mL/Kg. Animals in Peptide 16 (SEQ IDNO: 16)/lipid complex treatment groups received 15, 30 or 60 mg/kg givenevery second day by intravenous infusion. Approximately 0.5 mL of bloodwas drawn from the retro-orbital sinus under isoflorane anesthesia andcollected in tubes containing Na₃EDTA as an anticoagulant from cohortsof 3 animals per group at baseline and 0.0833, 0.5, 1, 2, 6, 12, 24 and48 hours post-dose on Day 0 and Day 26. Thus, each cohort of animals hadblood drawn at three different timepoints. Plasma was separatedfollowing centrifugation and stored frozen at −20° C. until analyzed atCovance (UK). Peptide levels were analyzed by LC-MS/MS. Toxicokineticparameters were determined from individual plasma concentrations bynon-compartmental analysis using Kinetica 4.4.1.

As shown in the FIGS. 16 and 17, the plasma levels of Peptide 16 (SEQ IDNO: 16) increased rapidly post-dose, then were quantifiable up to 6 hrfollowing the end of infusion in animals given the Peptide 16 (SEQ IDNO: 16)/lipid complex at 15 and 30 mg/kg doses. Detectable levels ofpeptide were observed up to 12 hrs in animals treated with 60 mg/kg inboth sexes. The phospholipid levels increased post dose, then returnedto baseline levels over a similar timeframe to that of the peptide. Freecholesterol (unesterified) increased post infusion in a dose dependentmanner indicative of cholesterol mobilization. This was followed by adecrease in cholesterol indicating that the Peptide 16 (SEQ ID NO:16)/lipid complex particles efficiently remove cholesterol fromcirculation. Similar patterns were observed on Day 0 and Day 26.

The mean toxicokinetic parameters for the Peptide 16 (SEQ ID NO:16)/lipid complex on Day 0 (first dose) and Day 26 (last dose) arepresented in Table 11 below:

TABLE 11 Peptide 16 (SEQ ID NO: 16)/lipid Complex ToxicokineticParameters in Rat^(†) Dose C_(max) T_(max) AUC₀₋₁₂ T_(1/2) CL Vd Day(mg/Kg) Sex (μg/mL) (h) (μg · h/mL) (h) (mL/Kg/h) (mL/Kg) Day 0 15 Male341 0.0833 851 1.36 18.0 35.4 Day 0 30 Male 663 0.0833 2291 1.28 13.124.1 Day 0 60 Male 1390 0.0833 7497 2.16 7.90 24.7 Day 0 15 Female 2870.0833 671 0.835 22.5 27.1 Day 0 30 Female 688 0.0833 2106 1.35 14.628.3 Day 0 60 Female 1427 0.0833 6689 1.72 8.93 22.1 Day 26 15 Male 4220.0833 1176 1.71 13.0 32.1 Day 26 30 Male 858 0.0833 3188 1.62 9.37 21.9Day 26 60 Male 1870 1.00 9889 2.56 5.86 21.6 Day 26 15 Female 386 0.0833841 1.01 18.1 26.3 Day 26 30 Female 815 0.0833 2490 1.41 12.3 25.1 Day26 60 Female 1537 0.0833 7804 1.79 7.64 19.7 ^(†)Parameters calculatedfrom Peptide 16 (SEQ ID NO: 16) levels in plasma over time.

The T_(max) was immediate post dose. The estimated half-life ofcirculating levels of Peptide 16 (SEQ ID NO: 16) was between 0.835 and2.56 hours in rats of both sexes, and it appeared to increase in a dosedependent manner. The clearance and volume of distribution decreasedwith increasing dose. Based on the volume of distribution it could beinferred that the Peptide 16 (SEQ ID NO: 16)/lipid complex was generallydistributed in plasma compartment (reference plasma volume in rat=30mL/Kg). See Davies, B. and Morris, T. Physiological parameters inlaboratory animals and human, Pharmaceutical Research, 10, 1093-1095,1993.

The increase in AUC_((0-12h)) and C_(max) with the increase in dose(based on the 15 mg/kg dose) is presented in Table 12. The C_(max)values were dose proportional in both sexes where as AUC_((0-12h))values increased more than a dose proportionally, suggesting longerresidence times of the Peptide 16 (SEQ ID NO: 16)/lipid complex in thecirculation with increasing dose.

TABLE 12 Increase in AUC and C_(max) with Increase in Dose of Peptide 16(SEQ ID NO: 16)/Lipid Complex Dose 15 mg/kg 30 mg/kg 60 mg/kg MalesFemales Males Females Males Females Day 0 Dose 1 1 2 2 4 4 IncrementIncrease — — 2.69 3.14 8.81 9.96 in AUC_((0-12 h)) Increase — — 1.94 2.44.07 4.98 in C_(max) Day 26 Dose 1 1 2 2 4 4 Increment Increase — — 2.712.96 8.4 9.28 in AUC_((0-12 h)) Increase — — 2.03 2.11 4.43 3.98 inC_(max)

There were no major sex-related differences in pharmacokinetic profiles,AUCs or C_(max) values following single dose and multiple doseadministration. Based on C_(max) and AUCs no accumulation of Peptide 16(SEQ ID NO: 16) or Peptide 16 (SEQ ID NO: 16)/lipid complex was observedduring the 4-week administration period.

c. Pharmacokinetic Studies in Monkeys

The toxicokinetics of the Peptide 16 (SEQ ID NO: 16)/lipid complex wereevaluated following dose administration in monkeys on Day 0 (First dose)and Day 26. Animals in the vehicle control group received 130 mM sodiumchloride in 12 mM phosphate buffer, pH 8.2, intravenously at 10 mL/Kg.Animals in the Peptide 16 (SEQ ID NO: 16)/lipid complex treatment groupsreceived 15, 30 or 60 mg/kg given every second day by intravenousinfusion. Blood was collected into tubes containing Na₃EDTA as ananticoagulant, at baseline, at the end of infusion, and then at 1, 2, 6,12, 24 and 48 hours post-dose on Day 0 and Day 26. At each time point,approximately 1 mL of blood was drawn from the femoral vessel, while theanimal was held restrained without any anesthesia. Plasma was separatedfollowing centrifugation and stored frozen at −20° C. until analyzed atCovance (UK). Peptide levels were analyzed by LC-MS/MS. Toxicokineticparameters were determined from individual plasma concentrations bynon-compartmental analysis using Kinetica 4.4.1.

As shown in the FIGS. 18 and 19, Peptide 16 (SEQ ID NO: 16) could bedetected in plasma for up to 12 hr following the end of infusion inanimals given the Peptide 16 (SEQ ID NO: 16)/lipid complex at 15 mg/kgin both sexes. Detectable levels of peptide were observed up to 24 hrsin animals treated with 30 and 60 mg/kg. The phospholipid levels alsoincreased post dose, then returned to baseline levels over a similartimeframe to that of the peptide. Free cholesterol (unesterified)increased post infusion in a dose dependent manner indicative ofcholesterol mobilization. This was followed by a decrease in cholesterolindicating that the Peptide 16 (SEQ ID NO: 16)/lipid complex particlesefficiently remove cholesterol from circulation. Similar patterns wereobserved on Day 0 and Day 26.

The mean toxicokinetic parameters for the Peptide 16 (SEQ ID NO:16)/lipid complex on Day 0 (first dose) and Day 26 (last dose) arepresented in Table 13 below:

TABLE 13 Peptide 16 (SEQ ID NO: 16)/Lipid Complex ToxicokineticParameters in Monkeys Dose C_(max) T_(max) AUC_(0-24 h) T_(1/2) CL VdDay (mg/Kg) Sex (μg/mL) (h) (μg · h/mL) (h) (mL/Kg/h) (mL/Kg) Day 0 15Male 341 0.0167 1346 2.42 11.50 39.6 Day 0 30 Male 735 0 4337 2.96 6.9029.3 Day 0 60 Male 1540 0 13787 4.58 4.27 28.1 Day 0 15 Female 365 01383 2.37 11.4 38.3 Day 0 30 Female 736 0 4337 3.04 6.81 29.4 Day 0 60Female 1508 0 13168 3.24 4.54 21.1 Day 26 15 Male 443 0 1539 2.66 10.0038.8 Day 26 30 Male 824 0 3890 2.19 8.58 26.3 Day 26 60 Male 1674 012182 2.82 5.07 20.8 Day 26 15 Female 408 0 1437 2.11 10.90 32.8 Day 2630 Female 690 0 3416 2.50 8.85 32.0 Day 26 60 Female 1608 0 13596 3.634.51 22.9 ^(†)Parameters calculated from Peptide 16 (SEQ ID NO: 16)levels in plasma over time. T = 0 is at the end of infusion.

The T_(max) was immediate post dose. The estimated half-life ofcirculating levels of Peptide 16 (SEQ ID NO: 16) was between 2.11 and4.58 hours in monkeys of both sexes, and it appeared to increase in adose dependent manner. The clearance and volume of distributiondecreased with increasing dose. Based on the volume of distribution itcould be inferred that Peptide 16 (SEQ ID NO: 16)/lipid complex isdistributed primarily in the plasma compartment (plasma volume inprimates=45 mL/Kg). See Davies, B. and Morris, T. Physiologicalparameters in laboratory animals and humans. Pharmaceutical Research,10, 1093-1095, 1993.

The increase in AUC_((0-24h)) and C_(max) with the increase in dose(based on the 15 mg/kg dose) is presented in Table 14. The C_(max)values were dose proportional in both sexes where as AUC_((0-24h))values increased in a more than a dose proportional manner, suggesting alonger residence time of the Peptide 16 (SEQ ID NO: 16)/lipid complex inthe circulation with increasing dose.

TABLE 14 Increase in AUC and C_(max) with Increase in Dose of Peptide 16(SEQ ID NO: 16)/Lipid Complex Dose 15 mg/kg 30 mg/kg 60 mg/kg MalesFemales Males Females Males Females Day 0 Dose 1 1 2 2 4 4 IncrementIncrease — — 3.22 3.31 10.2 9.52 in AUC_((0-24 h)) Increase — — 2.152.01 4.51 4.13 in C_(max) Day 26 Dose 1 1 2 2 4 4 Increment Increase — —2.53 2.38 7.91 9.46 in AUC_((0-24 h)) Increase — — 1.86 1.68 3.78 3.94in C_(max)

There were no major sex-related differences in pharmacokinetic profiles,AUCs or C_(max) values following single dose and multiple doseadministration.

Based on C_(max) and AUCs no accumulation of the Peptide 16 (SEQ ID NO:16)/lipid complex or Peptide 16 (SEQ ID NO: 16) was observed during the4-week administration period.

Example 24 Pharmacokinetic Studies on Peptide 16 (SEQ ID NO: 16) andPeptide 16 (SEQ ID NO: 16)/Lipid Complexes in Mice

Total cholesterol, unesterified cholesterol and cholesterol ester (asthe difference between total and unesterified cholesterol values) inplasma after injection of one of three peptide formulations weremeasured.

Peptide formulations: (A) Peptide 16 (SEQ ID NO: 16); (B) Peptide 16(SEQ ID NO: 16)/DPPC complex (1:2 weight ratio); (C) Peptide 16 (SEQ IDNO: 16)/DPPC complex (1:2.5 weight ratio). Formulations A, B, and C wereeach provided as solutions at a concentration of 15 mg/ml.

20 C57BI/6J mice were fasted for at least two weeks with a Rodent Dietwith 60% kcal % fat (Reseach diets—D12492). The drinking water wassupplemented with 5% glucose. Following 3 h fasting, the peptideformulations were dosed at 30 mg/kg (IV injection −50 μl) and the bloodwas sampled at 15, 30, 60, 120 and 240 minutes. One pre-dose sample wasperformed before the injection.

Plasma samples were analyzed for total cholesterol and unesterifiedcholesterol (kits from Biolabo—CEROOX-SOP002, CEROOX-SOP003). Thecholesterol ester was calculated as the difference between totalcholesterol and unesterified cholesterol.

The results are shown in FIGS. 20 and 21.

A number of references are disclosed herein, each of which isincorporated by reference herein in its entirety.

The following are some illustrative embodiments of the invention:

1. A 22- to 29-residue peptide having the following Formula IR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIor a pharmaceutically acceptable salt thereof, wherein:

X¹ is absent or a basic achiral amino acid residue, a basic D-amino acidresidue, or a basic L-amino acid residue;

X² is a basic achiral amino acid residue, a basic D-amino acid residue,or a basic L-amino acid residue;

X³ is an aliphatic achiral amino acid residue, an aliphatic D-amino acidresidue, or an aliphatic L-amino acid residue;

X⁴ is a basic achiral amino acid residue, a basic D-amino acid residue,or a basic L-amino acid residue;

X⁵ is Gln, Asn, D-Gln, D-Asn, or a basic achiral amino acid residue, abasic D-amino acid residue, or a basic L-amino acid residue;

X⁶ is a basic achiral amino acid residue, a basic D-amino acid residue,or a basic L-amino acid residue;

X⁷ is a hydrophobic achiral amino acid residue, a hydrophobic D-aminoacid residue, or a hydrophobic L-amino acid residue;

X⁸ is a hydrophobic achiral amino acid residue, a hydrophobic D-aminoacid residue, or a hydrophobic L-amino acid residue;

X⁹ is a hydrophilic achiral amino acid residue, a hydrophilic D-aminoacid residue, or a hydrophilic L-amino acid residue;

X¹⁰ is Leu, Trp, Gly, NaI, D-Leu, D-Trp, or D-NaI;

X¹¹ is Gly or an aliphatic achiral amino acid residue, an aliphaticD-amino acid residue, or an aliphatic L-aliphatic amino acid residue;

X¹² is a hydrophilic achiral amino acid residue, a hydrophilic D-aminoacid residue, or a hydrophilic L-amino acid residue;

X¹³ is a hydrophilic achiral amino acid residue, a hydrophilic D-aminoacid residue, or a hydrophilic L-amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu, Gly, or D-Leu;

X¹⁶ is an acidic achiral amino acid residue, an acidic D-amino acidresidue, or an acidic L-amino acid residue;

X¹⁷ is a hydrophilic achiral amino acid residue, a hydrophilic D-aminoacid residue, or a hydrophilic L-amino acid residue;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is an acidic achiral amino acid residue, an acidic D-amino acidresidue, or an acidic L-amino acid residue;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an aliphatic achiral amino acid residue, an aliphatic D-aminoacid residue, or an aliphatic L-amino acid residue; and

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or a sequence of 1 to 7 amino acid residues, wherein eachresidue of the sequence is independently an achiral, D-, or L-amino acidresidue;

Y² is absent or a sequence of 1 to 7 amino acid residues, wherein eachresidue of the sequence is independently an achiral, D-, or L-amino acidresidue;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein: (a) all amino acid residues, other than the terminal amino acidresidues and residues immediately adjacent to the terminal amino acidresidues, are achiral or L-amino acid residues; or (b) all amino acidresidues, other than the terminal amino acid residues and residuesimmediately adjacent to the terminal amino acid residues, are achiral orD-amino acid residues.2. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 1, wherein:

X³ is Leu or D-Leu;

X⁷ is Leu, Gly, NaI, D-Leu, or D-NaI;

X⁸ is Ala, NaI, Trp, Gly, Leu, Phe, D-Ala, D-NaI, D-Trp, D-Leu, orD-Phe;

X¹¹ is Leu, Gly, Aib, or D-Leu; and

X²² is Ala, Leu, Val, D-Ala, D-Leu, or D-Val.

3. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 1, wherein:

X¹ is absent, Lys, or D-Lys;

X² is Lys, Orn, D-Lys, or D-Orn;

X⁴ is Lys, Orn, D-Lys, or D-Orn;

X⁵ is Gln, Asn, Lys, Orn, D-Gln, D-Asn, D-Lys, or D-Orn;

X⁶ is Gln, Asn, Lys, Orn, D-Gln, D-Asn, D-Lys, or D-Orn;

X⁹ is Asp, Glu, D-Asp, or D-Glu;

X¹² is Glu, Asp, D-Asp, or D-Glu;

X¹³ is Asn, Gln, D-Asn or D-Gln;

X¹⁶ is Asp, Glu, D-Asp, or D-Glu;

X¹⁷ is Lys, Arg, Orn, D-Lys, D-Arg, or D-Orn; and

X²⁰ is Asp, Glu, D-Asp, or D-Glu.

4. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 3, wherein X¹⁸ is Phe or D-Phe.

5. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 1, wherein the peptide is a 22- or 23-residue peptide.

6. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 5, wherein R¹ is H and R² is OH.

7. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 5, wherein:

X¹ is absent, Lys or D-Lys;

X² is Lys, Orn, D-Lys, or D-Orn;

X³ is Leu or D-Leu;

X⁴ is Lys, Orn, D-Lys, or D-Orn;

X⁵ is Gln, Asn, Lys, Orn, D-Gln, D-Asn, D-Lys, or D-Orn;

X⁶ is Lys, Orn, D-Lys, or D-Orn;

X⁷ is Gly, Leu, NaI, D-Leu, or D-NaI;

X⁸ is Ala, NaI, Trp, Leu, Phe, Gly, D-Ala, D-NaI, D-Trp, D-Leu, orD-Phe;

X⁹ is Asp, Glu, D-Asp, or D-Glu;

X¹¹ is Gly, Leu, Aib, or D-Leu;

X¹² is Glu, Asp, D-Glu, or D-Asp;

X¹³ is Asn, Gln, D-Asn, or D-Gln;

X¹⁶ is Asp, Glu, D-Asp, or D-Glu;

X¹⁷ is Lys, Arg, Orn, D-Lys, D-Arg, or D-Orn;

X²⁰ is Asp, Glu, D-Asp, or D-Glu; and

X²² is Ala, Val, Leu, D-Ala, D-Val, or D-Leu.

8. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 7, wherein: X⁵ is Gln, Asn, D-Gln, or D-Asn and X⁶ is Lys,Orn, D-Lys, or D-Orn; or X⁵ is Lys, Orn, D-Lys, or D-Orn and X⁶ is Gln,Asn, D-Gln, or D-Asn.

9. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 7, wherein X¹ is absent and the peptide is a 22-residuepeptide.

10. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 9, wherein) each of X⁷, X⁸, X¹⁰, X¹¹, X¹⁴, and X¹⁵ is otherthan Gly.

11. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 9, wherein only one of X⁷, X⁸, X¹⁰, X¹¹, X¹⁴, and X¹⁵ is Gly.

12. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 9, wherein:

X² and X⁴ are both Lys, Orn, D-Lys, or D-Orn;

X⁵ is Gln, Lys, D-Gln, or D-Lys;

X⁹ is an acidic achiral amino acid residue, an acidic D-amino acidresidue, or an acidic L-amino acid residue;

X¹² is Glu, Asn, Gln, Arg, D-Glu, D-Asn, D-Gln, or D-Arg;

X¹³ is Glu, Asn, Gln, Arg, D-Glu, D-Asn, D-Gln, or D-Arg;

X¹⁶ is an acidic achiral amino acid residue, an acidic D-amino acidresidue, or an acidic L-amino acid residue;

X¹⁷ is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn;

X²¹ is Leu or D-Leu; and

X²² is Ala, Val, Leu, D-Ala, D-Val, or D-Leu.

13. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 1, wherein the peptide is:

(SEQ. ID. NO. 2)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 3)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 4)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 5)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 6)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 7)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 8)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp; (SEQ. ID. NO. 9)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 10)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 11)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 12)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 13)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 14)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 15)Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 16)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 18)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 19)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 20)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 21)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 22)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 23)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 24)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 25)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 26)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Inp; (SEQ. ID. NO. 28)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp; (SEQ. ID. NO. 29)Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 30)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 31)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 32)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 33)Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 36)Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 40)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp; (SEQ. ID. NO. 94)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 95)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 96)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 97)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 98)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 99)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 100)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip; (SEQ. ID. NO. 101)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip; (SEQ. ID. NO. 102)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 103)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 104)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 105)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 106)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 107)Lys-Leu-Lys-Gln-Lys-Leu-Nal-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 108)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 110)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 111)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 112)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 113)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 114)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 115)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 116)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 117)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip; (SEQ. ID. NO. 118)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Nip; (SEQ. ID. NO. 120)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Aib-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip; (SEQ. ID. NO. 121)Lys-Leu-Lys-Gln-Lys-Leu-Leu-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 122)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Nal-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 123)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Trp-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 124)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Om-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 125)Lys-Leu-Lys-Gln-Lys-Leu-Phe-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 128)Lys-Leu-Lys-Gln-Arg-Leu-Ala-Asp-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip; or (SEQ. ID. NO. 132)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Gln-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

14. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 5, wherein the peptide is a 23-residue peptide.

15. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 14, wherein the peptide is:

(SEQ. ID. NO. 17) Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 109)Lys-Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

16. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 5, wherein X¹ is absent and the peptide is a 22-residuepeptide.

17. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein the peptide is:

(SEQ. ID. NO. 34) Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 35)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 126)Lys-Leu-Lys-Lys-Gln-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Nip; or (SEQ. ID. NO. 127)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Asn-Phe-Leu-Glu-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

18. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein:

X⁹ is Gln, Lys, D-Gln, D-Lys, an acidic achiral amino acid residue, anacidic D-amino acid residue, or an acidic L-amino acid residue;

X¹² is Asn, D-Asn, an acidic achiral amino acid residue, an acidicD-amino acid residue, or an acidic L-amino acid residue; and

X¹⁷ is Asn, Glu, D-Asn, D-Glu, a basic achiral amino acid residue, abasic D-amino acid residue, or a basic L-amino acid residue.

19. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein:

X⁹ is Gln, Lys, D-Gln, D-Lys, an acidic achiral amino acid residue, anacidic D-amino acid residue, or an acidic L-amino acid residue;

X¹² is Asn, D-Asn, an acidic achiral amino acid residue, an acidicD-amino acid residue, or an acidic L-amino acid residue; and

X¹⁷ is Asn, Glu, D-Asn, D-Glu, a basic achiral amino acid residue, abasic D-amino acid residue, or a basic L-amino acid residue.

20. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein:

X² is Lys, Orn, D-Lys, or D-Orn;

X³ is Leu or D-Leu;

X⁴ is Lys, Orn, D-Lys, or D-Orn;

X⁵ is Lys, Orn, Gln, Asn, D-Lys, D-Orn, D-Gln, or D-Asn;

X⁶ is Lys, Orn, D-Lys, or D-Orn;

X⁷ is Leu, Gly, NaI, D-Leu, or D-NaI;

X⁸ is Ala, Trp, Gly, Leu, Phe, NaI, D-Ala, D-Trp, D-Leu, D-Phe, orD-NaI;

X⁹ is Asp, Glu, Gln, Lys, D-Asp, D-Glu, D-Gln, or D-Lys;

X¹¹ is Leu, Gly, Aib, or D-Leu;

X¹² is Asp, Glu, Asn, D-Asp, D-Glu, or D-Asn;

X¹³ is Asn, Gln, Glu, Arg, D-Asn, D-Gln, D-Glu, or D-Arg;

X¹⁶ is Asp, Glu, D-Asp, or D-Glu;

X¹⁷ is Lys, Arg, Orn, Asn, Glu, D-Lys, D-Arg, D-Orn, D-Asn, or D-Glu;

X²⁰ is Asp, Glu, D-Asp, or D-Glu; and

X²² is Ala, Val, Leu, D-Ala, D-Val, or D-Leu.

21. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein:

X⁹ is Glu or D-Glu;

X¹² is Glu or D-Glu;

X¹³ is Asn, Glu, D-Asn, or D-Glu;

X¹⁴ is Leu or D-Leu;

X¹⁵ is Leu or D-Leu;

X¹⁶ is Glu or D-Glu;

X¹⁷ is Arg, Lys, D-Arg, or D-Lys;

X¹⁸ is Phe or D-Phe;

X¹⁹ is Leu or D-Leu;

X²¹ is Leu or D-Leu; and

X²² is Val or D-Val.

22. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X¹¹ is Gly and each of X⁷, X⁸, X¹⁰, X¹⁴, and X¹⁵is other than Gly.

23. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein:

X² is Lys, Orn, D-Lys, or D-Orn;

X³ is Leu or D-Leu;

X⁴ is Lys, Orn, D-Lys, or D-Orn;

X⁵ is Gln or D-Gln;

X⁶ is Lys, Orn, D-Lys, or D-Orn;

X⁷ is Leu, NaI, D-Leu, or D-NaI;

X⁸ is Ala, Trp, D-Ala, or D-Trp;

X⁹ is Glu or D-Glu;

X¹⁰ is Leu or D-Leu;

X¹¹ is Gly;

X¹² is Glu or D-Glu;

X¹³ is Asn or D-Asn;

X¹⁴ is Leu, Trp, D-Leu, or D-Trp;

X¹⁵ is Leu or D-Leu;

X¹⁶ is Glu or D-Glu;

X¹⁷ is Arg or D-Arg;

X¹⁸ is Phe or D-Phe;

X¹⁹ is Leu, Phe, D-Leu, or D-Phe;

X²⁰ is Asp, Glu, D-Asp, or D-Glu;

X²¹ is Leu or D-Leu; and

X²² is Val or D-Val.

24. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 20, wherein the peptide is:

(SEQ. ID. NO. 2) Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 3)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 4)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 5)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 6)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 7)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 8)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp; (SEQ. ID. NO. 9)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp; (SEQ. ID. NO. 94)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 95)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 96)Lys-Leu-Lys-Gln-Lys-Nal-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 97)Lys-Leu-Lys-Gln-Lys-Leu-Trp-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 98)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 99)Orn-Leu-Orn-Gln-Orn-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; (SEQ. ID. NO. 100)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip; or (SEQ. ID. NO. 101)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Gly-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

25. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X¹⁵ is Gly and each of X⁷, X⁸, X¹⁰, X¹¹ and X¹⁴is other than Gly.

26. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 25, wherein the peptide is:

(SEQ. ID. NO. 10) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 102)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Gly-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

27. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X¹⁴ is Gly and each of X⁷, X⁸, X¹⁰, X¹¹, and X¹⁵is other than Gly.

28. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 27, wherein the peptide is:

(SEQ. ID. NO. 11) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 103)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

29. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X¹⁰ is Gly and each of X⁷, X⁸, X¹¹, X¹⁴, and X¹⁵is other than Gly.

30. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 29, wherein the peptide is:

(SEQ. ID. NO. 12) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 104)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Gly-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

31. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X⁸ is Gly and each of X⁷, X¹⁰, X¹¹, X¹⁴, and X¹⁵is other than Gly.

32. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 31, wherein the peptide is:

(SEQ. ID. NO. 13) Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 105)Lys-Leu-Lys-Gln-Lys-Leu-Gly-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

33. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 16, wherein X⁷ is Gly and each of X⁸, X¹⁰, X¹¹, X¹⁴, and X¹⁵is other than Gly.

34. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 33, wherein the peptide is:

(SEQ. ID. NO. 14) Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 106)Lys-Leu-Lys-Gln-Lys-Gly-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

35. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 1, wherein the peptide is:

(SEQ. ID. NO. 16) Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; or (SEQ. ID. NO. 108)Lys-Leu-Lys-Gln-Lys-Leu-Ala-Glu-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

a pharmaceutically acceptable salt of one of the foregoing.

36. A 15- to 22-residue peptide having the following Formula IIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—Y²—R²,  FormulaIIand pharmaceutically acceptable salts thereof, wherein:

X¹ is an achiral, D-, or L-basic amino acid residue;

X² is Leu or D-Leu;

X³ is an achiral, D-, or L-basic amino acid residue;

X⁴ is Gln, Asn, D-Gln, or D-Asn;

X⁵ is Leu, D-Leu, or an achiral, D-, or L-basic amino acid amino acidresidue;

X⁶ is Leu, Trp, Phe, D-Leu, D-Trp, or D-Phe;

X⁷ is an achiral, D-, or L-acidic amino acid residue;

X⁸ is Asn, D-Asn, or an achiral, D-, or L-acidic amino acid residue;

X⁹ is Leu, Trp, D-Leu, or D-Trp;

X¹⁰ is Leu, Trp, D-Leu, or D-Trp;

X¹¹ is an achiral, D-, or L-acidic amino acid residue;

X¹² is an achiral, D-, or L-basic amino acid residue;

X¹³ is Leu, Phe, D-Leu, or D-Phe;

X¹⁴ is Leu, Phe, D-Leu, or D-Phe;

X¹⁵ is an achiral, D-, or L-acidic amino acid residue;

X¹⁶ is Leu or D-Leu;

X¹⁷ is an achiral, D-, or L-aliphatic amino acid residue;

X¹⁸ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 4 residues;

Y² is absent;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein zero to three of residues X¹ to X¹⁷ are absent; and

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is an D-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is an L-aminoacid residue.

37. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 36, wherein X¹⁷ is Ala, Leu, Val, D-Ala, D-Leu, or D-Val.

38. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 36, wherein:

X¹ is His, Lys, Arg, D-His, D-Lys, or D-Arg;

X³ is Lys, Arg, Orn, D-Lys, D-Arg, or D-Orn;

X⁵ is Lys, Arg, Orn, D-Lys, D-Arg, or D-Orn;

X⁷ is Glu or D-Glu;

X⁸ is Asn, Glu, D-Asn, or D-Glu;

X¹¹ is Asp, Glu, D-Asp, or D-Glu;

X¹² is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn; and

X¹⁵ is Asp, Glu, D-Asp, or D-Glu.

39. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 38, wherein X¹³ is Phe or D-Phe.

40. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 36, wherein the peptide is an 18-residue peptide.

41. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 40, wherein R¹ is H and R² is OH.

42. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 41, wherein:

X¹ is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn;

X³ is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn;

X⁵ is Arg, Lys, Orn, D-Arg, D-Lys, or D-Orn;

X⁷ is Glu or D-Glu;

X⁸ is Glu, Asn, D-Glu, or D-Asn;

X¹¹ is Glu, Asp, D-Glu, or D-Asp;

X¹² is Arg, Lys, Orn, D-Arg, D-Lys, or D-Om;

X¹⁵ is Asp, Glu, D-Asp, or D-Glu; and

X¹⁷ is Ala, Val, Leu, D-Ala, D-Val, or D-Leu.

43. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 36, wherein the peptide is:

(SEQ. ID. NO. 53) Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 54)Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp; (SEQ. ID. NO. 145)Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip; or (SEQ. ID. NO. 146)Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip, or

or a pharmaceutically acceptable salt of one of the foregoing.

44. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 36, wherein the peptide is:

(SEQ. ID. NO. 65)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 66)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 67)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 68)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 69)H3C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 70)H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 71)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Inp-NH₂; (SEQ. ID. NO. 72)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 73)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Inp-NH₂; (SEQ. ID. NO. 74)H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂; (SEQ. ID. NO. 75)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 76)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Trp-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 77)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Inp-NH₂; (SEQ. ID. NO. 78)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 79)H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂; (SEQ. ID. NO. 80)H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 81)H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 82)H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Inp-NH₂; (SEQ. ID. NO. 83)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 84)H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂; (SEQ. ID. NO. 87)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Inp-NH₂; (SEQ. ID. NO. 88)H₃C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-A sp-Leu-Val-Inp-NH₂;(SEQ. ID. NO. 89)H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Inp-NH₂;(SEQ. ID. NO. 157)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Leu-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 158)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 159)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 160)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Glu-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 161)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 162)H₃C(O)C-Lys-Leu-Lys-Asn-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 163)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Leu-Nip-NH₂; (SEQ. ID. NO. 164)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Trp-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 165)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Asp-Leu-Leu-Nip-NH₂; (SEQ. ID. NO. 166)H₃C(O)C-Arg-Leu-Lys-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂; (SEQ. ID. NO. 167)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Phe-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 168)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Leu-Nip-NH₂; (SEQ. ID. NO. 169)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Glu-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 170)H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Leu-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂; (SEQ. ID. NO. 171)H₃C(O)C-Orn-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 172)H₃C(O)C-Lys-Leu-Orn-Gln-Orn-Leu-Glu-Glu-Leu-Leu-Glu-Orn-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 173)H₃C(O)C-Lys-Leu-Arg-Gln-Arg-Phe-Glu-Glu-Leu-Leu-Asp-Lys-Phe-Leu-Glu-Leu-Ala-Nip-NH₂; (SEQ. ID. NO. 174)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Trp-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 175)H₃C(O)C-Lys-Leu-Lys-Gln-Leu-Leu-Glu-Asn-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 176)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Gly-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂; (SEQ. ID. NO. 179)H₃C(O)C-Lys-Leu-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Lys-Phe-Leu-Glu-Leu-Leu-Nip-NH₂; (SEQ. ID. NO. 180)H3C(O)C-Lys-Leu-Lys-Gln-Glu-Leu-Leu-Glu-Arg-Phe-Leu-A sp-Leu-Val-Nip-NH₂;or (SEQ. ID. NO. 181)H₃C(O)H₃C(O)H₃C(O)H₃C(O)C-Lys-Gln-Lys-Leu-Glu-Glu-Leu-Leu-Glu-Arg-Phe-Leu-Asp-Leu-Val-Nip-NH₂,

or a pharmaceutically acceptable salt of one of the foregoing.

45. A 22- to 29-residue peptide having the following Formula IIIR¹—Y¹—X¹—X²—X³—X⁴—X⁵—X⁶—X⁷—X⁸—X⁹—X¹⁰—X¹¹—X¹²—X¹³—X¹⁴—X¹⁵—X¹⁶—X¹⁷—X¹⁸—X¹⁹—X²⁰—X²¹—X²²—X²³—Y²—R²  FormulaIIIor a pharmaceutically acceptable salt thereof, wherein:

X¹ is absent or an achiral, D-, or L-basic amino acid residue;

X² is an achiral, D-, or L-basic amino acid residue;

X³ is Leu or D-Leu;

X⁴ is an achiral, D-, or L-basic amino acid residue;

X⁵ is an achiral, D-, or L-basic amino acid residue;

X⁶ is Gln, Asn, D-Gln, or D-Asn;

X⁷ is Leu or D-Leu;

X⁸ is Ala or D-Ala;

X⁹ is Asp or D-Asp;

X¹⁰ is Leu, Phe, Gly, D-Leu, or D-Phe;

X¹¹ is Gly, Leu, or D-Leu;

X¹² is Arg or D-Arg;

X¹³ is an achiral, D-, or L-acidic amino acid residue;

X¹⁴ is Leu, Trp, Gly, D-Leu, or D-Trp;

X¹⁵ is Leu or D-Leu;

X¹⁶ is Gln or D-Gln;

X¹⁷ is Glu, Leu, D-Glu, or D-Leu;

X¹⁸ is Leu, Phe, D-Leu, or D-Phe;

X¹⁹ is an achiral, D-, or L-aliphatic amino acid residue;

X²⁰ is Glu or D-Glu;

X²¹ is Leu, Phe, D-Leu, or D-Phe;

X²² is an achiral, D-, or L-aliphatic amino acid residue;

X²³ is Inp, Nip, azPro, Pip, azPip, D-Nip, or D-Pip;

Y¹ is absent or an amino acid sequence having from 1 to 7 residues;

Y² is absent or an amino acid sequence having from 1 to 7 residues;

R¹ is H or an amino protecting group;

R² is OH or a carboxyl protecting group;

wherein:

a) each chiral amino acid residue is an L-amino acid residue;

b) each chiral amino acid residue is a D-amino acid residue;

c) each chiral amino acid residue is an L-amino acid residue, exceptthat one or more of each chiral terminal amino acid residue and eachchiral amino acid residue immediately adjacent thereto is a D-amino acidresidue; or

d) each chiral amino acid residue is a D-amino acid residue, except thatone or more of each chiral terminal amino acid residue and each chiralamino acid residue immediately adjacent thereto is an L-amino acidresidue.

46. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 45, wherein the peptide is a 22- or 23-residue peptide.

47. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 46, wherein the peptide is a 22-residue peptide.

48. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X²² is Val, Leu, D-Val, or D-Leu.

49. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein:

X² is Lys or D-Lys;

X⁴ is Lys or D-Lys;

X⁵ is Lys or D-Lys;

X¹³ is Glu or D-Glu;

X¹⁸ is Phe or D-Phe;

X¹⁹ is Leu or D-Leu; and

X²² is Ala, Leu, Val, D-Ala, D-Leu, or D-Val.

50. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein:

X² is Lys or D-Lys;

X⁴ is Lys or D-Lys;

X⁵ is Lys or D-Lys;

X¹³ is Glu or D-Glu;

X¹⁸ is Phe or D-Phe;

X¹⁹ is Leu or D-Leu; and

X²² is Ala, Leu, Val, D-Ala, D-Leu, or D-Val.

51. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X¹³ and X¹⁷ are Glu or D-Glu.

52. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 46, wherein:

X¹ is absent;

X² is Lys or D-Lys;

X⁴ is Lys or D-Lys;

X⁵ is Lys or D-Lys;

X¹⁸ is Phe or D-Phe;

X¹⁹ is Leu or D-Leu; and

X²² is Val or D-Val.

53. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X¹³ or X¹⁷ is Glu or D-Glu.

54. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X²² is Val or D-Val and X⁶ is Gln or D-Gln.

55. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X²² is Val or D-Val or X⁶ is Gln or D-Gln.

56. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein only one of X¹⁰, X¹¹ and X¹⁴ is Gly.

57. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 45, wherein the peptide is:

Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-Inp(SEQ. ID. NO. 197); or

Lys-Leu-Lys-Lys-Gln-Leu-Ala-Asp-Leu-Leu-Arg-Glu-Leu-Leu-Gln-Glu-Phe-Leu-Glu-Leu-Val-Nip(SEQ. ID. NO. 211),

or a pharmaceutically acceptable salt of one of the foregoing.

58. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X¹⁰ is Gly and X¹⁷ is Glu or D-Glu.

59. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein each of X¹⁰, X¹¹ and X¹⁴ is other than Gly.

60. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 47, wherein X¹⁷ is Leu or D-Leu.

61. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 60, wherein X¹⁴ is Trp or D-Trp and X¹⁰ is Leu, Phe, D-Leu,or D-Phe.

62. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 60, wherein X¹⁴ is Trp or D-Trp or X¹⁰ is Leu, Phe, D-Leu, orD-Phe.

63. The peptide or pharmaceutically acceptable salt of the peptide ofembodiment 45, wherein R¹ is H and R² is OH.

64. The peptide of any one of embodiments 1 to 63, wherein the peptideis in the form of a pharmaceutically acceptable salt.

65. The peptide of embodiment 64, wherein the salt is a metal salt ororganic amine salt.

66. The peptide of embodiment 65, wherein the metal is an alkali metalor alkaline earth metal.

67. The peptide of embodiment 65, wherein the metal is lithium, sodium,potassium, magnesium, calcium, aluminum or zinc.

68. The peptide of embodiment 65, wherein the organic amine istriethylamine, ethanolamine, diethanolamine, triethanolamine,morpholine, N-methylpiperidine, N-ethylpiperidine, or dibenzylamine.

69. The peptide of embodiment 64, wherein the salt is an acid additionsalt.

70. The peptide of embodiment 69, wherein the acid addition salt is ahydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfite,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, tartrate, bitartrate, ascorbate, gentisinate, gluconate,glucaronate, saccarate, formate, benzoate, glutamate, pantothenate,acetate, fumarate, succinate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluoylsulfonate, citrate, or maleate salt.71. The peptide or pharmaceutically acceptable salt of the peptide ofany one of embodiments 1 to 63, wherein R¹ is an amino protecting group.72. The peptide or pharmaceutically acceptable salt of the peptide ofclaim 71, wherein the amino protecting group is dansyl; methoxycarbonyl;ethoxycarbonyl; 9-fluorenylmethoxycarbonyl; 2-chloroethoxycarbonyl;2,2,2-trichloroethoxycarbonyl; 2-phenylethoxycarbonyl; t-butoxycarbonyl;benzyloxycarbonyl; p-methoxybenzyloxycarbonyl; p-nitrobenzyloxycarbonyl;o-nitrobenzyloxycarbonyl; p-bromobenzyloxycarbonyl;p-chlorobenzyloxycarbonyl; p-iodobenzyloxycarbonyl;2,4-dichlorobenzyloxycarbonyl; diphenylmethoxycarbonyl;3,5-dimethoxybenzyloxycarbonyl; phenoxycarbonyl;2,4,6-tri-t-butylpenoxycarbonyl; 2,4,6-trimethylbenzyloxycarbonyl;formyl; acetyl; chloroacetyl; trichloroacetyl; trifluoroacetyl;phenylacetyl; picolinoyl; benzoyl; p-phenylbenzoyl; phthaloyl; methyl;t-butyl; allyl; [2-(trimethylsilyl)ethoxy]methyl; 2,4-dimethoxybenzyl;2,4-dinitrophenyl; benzyl; 4-methoxybenzyl; diphenylmethyl;triphenylmethyl; benzenesulfenyl; o-nitrobenzenesulfenyl;2,4-dinitrobenzenesulfenyl; p-toluenesulfonyl; benzenesulfonyl;2,3,6-trimethyl-4-methoxybenzenesulfonyl;2,4,6-trimethoxybenzenesulfonyl; 2,6-dimethyl-4-methoxybenzenesulfonyl;pentamethylbenzenesulfonyl; 4-methoxybenzenesulfonyl;2,4,6-trimethylbenzenesulfonyl; or benzylsulfonyl.73. The peptide or pharmaceutically acceptable salt of the peptide ofany one of embodiments 1 to 63, wherein R² is a carboxyl protectinggroup.74. The peptide or pharmaceutically acceptable salt of the peptide ofclaim 73, wherein the carboxyl protecting group is methoxy; ethoxy;9-fluorenylmethoxy; methoxymethoxy; methylthiomethoxy;tetrahydropyranoxy; tetrahydrofuranoxy; methoxyethoxymethoxy;benzyloxymethoxy; phenacyloxy; p-bromophenacyloxy; α-methylphenacyloxy;p-methoxyphenacyloxy; desyloxy; 2-chloroethoxy; 2,2,2-thrichloroethoxy,2-methylthioethoxy; 2-(ptoluenesulfonyl)methoxy; t-butoxy; cyclopentoxy;cyclohexoxy; allyloxy; methallyloxy; cinnamoxy; α-methylcinnamoxy;phenoxy; 2,6-dimethylphenoxy; 2,6-diisopropylphenoxy; benzyloxy;triphenylmethoxy; diphenylmethoxy; 2,4,6-trimethylbenzyloxy;p-bromobenzyloxy; o-nitrobenzyloxy; N,N-dimethylamido; pyrrolidinyl; orpiperidinyl.75. The peptide or pharmaceutically acceptable salt of the peptide ofany one of embodiments 1 to 63, wherein one or more of the peptide's—NH₂ or —COOH groups are protected with a protecting group.76. A composition comprising an effective amount of the peptide orpharmaceutically acceptable salt of the peptide of any one ofembodiments 1 to 75, and a pharmaceutically acceptable carrier orvehicle.77. A method for treating or preventing dyslipidemia, comprisingadministering an effective amount of the peptide or a pharmaceuticallyacceptable salt of the peptide of any one of embodiments 1 to 75 to amammal in need thereof.78. The method of embodiment 77, wherein the dyslipidemia ishyperproteinemia, high low-density lipoprotein serum concentration, highvery low-density lipoprotein serum concentration, hyperlipidemia, lowhigh-density lipoprotein serum concentration, hypocholesterolemia,Abetalipoproteinemia, ApoA-I deficiency, or Tangier disease.79. The method of embodiment 77, wherein the dyslipidemia ishyperlipidemia, hypercholesterolemia, ApoA-I deficiency, orhypertriglyceridemia.80. The method of embodiment 77, wherein the treating comprisesincreasing serum high density lipoprotein concentration.81. A method for treating or preventing a cardiovascular disease,comprising administering an effective amount of the peptide orpharmaceutically acceptable salt of the peptide of any one ofembodiments 1 to 75 to a mammal in need thereof.82. The method of claim 81, wherein the cardiovascular disease ismetabolic syndrome, ischemic heart disease, atherosclerosis, restenosis,endotoxemia, congestive heart failure, circulatory shock,cardiomyopathy, cardiac transplant, myocardial infarction, a cardiacarrhythmia, supraventricular tachycardia, atrial flutter, paroxysmalatrial tachycardia, aneurysm, angina, cerebrovascular accident,peripheral vascular disease, cerebrovascular disease, kidney disease,atherogenesis, atherosclerosis, acute pancreatitis, or coronary arterydisease.83. The method of claim 81, wherein the cardiovascular disease isatherosclerosis, restenosis, or a metabolic syndrome.84. A method for treating or preventing endothelial dysfunction,comprising administering an effective amount of the peptide or apharmaceutically acceptable salt of the peptide of any one ofembodiments 1 to 75 to a mammal in need thereof.85. A method for treating or preventing a macrovascular disorder,comprising administering an effective amount of the peptide or apharmaceutically acceptable salt of the peptide of any one ofembodiments 1 to 75 to a mammal in need thereof.86. The method of claim 85, wherein the macrovascular disorder istransient ischaemic attack, stroke, angina, myocardial infarction,cardiac failure, or peripheral vascular disease.87. A method for treating or preventing a microvascular disorder,comprising administering an effective amount of the peptide or apharmaceutically acceptable salt of the peptide of any one ofembodiments 1 to 75 to a mammal in need thereof.88. The method of claim 87, wherein the microvascular disorder isdiabetic retinopathy, microalbuminuria, macroalbuminuria, end stagerenal disease, erectile dysfunction, autonomic neuropathy, peripheralneuropathy, osteomyelitis, or lower limb ischaemia.89. The method of any one of embodiments 77 to 88, wherein the mammal isa human.90. The method of any one of embodiments 77 to 89, wherein theadministering is done orally, intravenously, intramuscularly,intrathecally, subcutaneously, sublingually, nasally, cutaneously,transdermally, ocularly, or by inhalation.

The invention claimed is:
 1. A peptide having the sequence of SEQ ID NO:108, or a pharmaceutically acceptable salt thereof.
 2. A compositioncomprising an effective amount of the peptide or pharmaceuticallyacceptable salt of the peptide of claim 1, and a pharmaceuticallyacceptable carrier or vehicle.
 3. A peptide/lipid complex, wherein thepeptide is the peptide or pharmaceutically acceptable salt of thepeptide of claim
 1. 4. The peptide/lipid complex of claim 3, wherein thelipid comprises a phospholipid.
 5. The peptide/lipid complex of claim 4,wherein the phospholipid is one or more of sphingomyelin,dipalmitoylphosphatidylcholine (DPPC) anddipalmitoylphosphatidylglycerol (DPPG).
 6. The peptide/lipid complex ofclaim 4, wherein the lipid is a mixture of sphingomyelin anddipalmitoylphosphatidylcholine (DPPC) or dipalmitoylphosphatidylglycerol(DPPG).
 7. The peptide/lipid complex of claim 4, wherein the lipid is amixture of sphingomyelin, dipalmitoylphosphatidylcholine (DPPC) anddipalmitoylphosphatidylglycerol (DPPG).
 8. The peptide/lipid complex ofclaim 6, wherein the ratio of total peptide to lipid is about 1:about0.5 to about 1:about
 5. 9. The peptide/lipid complex of claim 7, whereinthe ratio of total peptide to lipid is about 1:about 0.5 to about1:about
 5. 10. The peptide/lipid complex of claim 7, wherein thepeptide:sphingomyelin:DPPC:DPPG weight ratio is 1:1.2125:1.2125:0.075.11. A composition comprising the peptide/lipid complex of claim 3, and apharmaceutically acceptable carrier or vehicle.
 12. A compositioncomprising the peptide/lipid complex of claim 4, and a pharmaceuticallyacceptable carrier or vehicle.
 13. A composition comprising thepeptide/lipid complex of claim 5, and a pharmaceutically acceptablecarrier or vehicle.
 14. A composition comprising the peptide/lipidcomplex of claim 6, and a pharmaceutically acceptable carrier orvehicle.
 15. A composition comprising the peptide/lipid complex of claim7, and a pharmaceutically acceptable carrier or vehicle.
 16. Acomposition comprising the peptide/lipid complex of claim 8, and apharmaceutically acceptable carrier or vehicle.
 17. A compositioncomprising the peptide/lipid complex of claim 9, and a pharmaceuticallyacceptable carrier or vehicle.
 18. A composition comprising thepeptide/lipid complex of claim 10, and a pharmaceutically acceptablecarrier or vehicle.